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THE  LIBRARY 

OF 

THE  UNIVERSITY 

OF  CALIFORNIA 


PRESENTED  BY 

PROF.  CHARLES  A.  KOFOID  AND 

MRS.  PRUDENCE  W.  KOFOID 

PUBLIC 
HEALTH 
LIBRARY 


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CLINICAL    HEMATOLOGY 
DaCOSTA 


CLINICAL 

HEMATOLOGY 

A   PRACTICAL   GUIDE 

TO    THE 

EXAMINATION    OF   THE    BLOOD  WITH 
REFERENCE   TO    DIAGNOSIS. 


By 


JOHN    C.  ^aCOSTA,  Jr.,  M.D. 

ASSISTANT    DEMONSTRATOR    OF    CLINICAL    MEDICINE,    JEFFERSON    MEDICAL   COLLBGE 
HEMATOLOGIST    TO    THE    GERMAN    HOSPITAL,    ETC. 


Containing  Eight  Full-Page  Colored  Plates,  Three  Charts, 
AND  Forty-Eight  other  Illustrations. 


PHILADELPHIA : 
P.    BLAKISTON'S   SON    &    CO. 

IOI2    WALNUT    street 
1902 


Copyright,  1901, 
P.  Blakiston's  Son  &  Co. 


i^i'l 


? Lib  He 

Lih 


TO 

MY    FATHER, 
JOHN   C    DaCOSTA,  M.D., 

THESE  PAGES  ARE 

AFFECTIONATELY    DEDICATED. 


ivi37eQ5£ 


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PREFACE. 

This  book,  designed  as  a  practical  guide  to  the  examination  of 
the  blood  by  methods  adapted  to  routine  clinical  work,  repre- 
sents an  endeavor  to  recount  the  salient  facts  of  hematology  as 
they  are  understood  at  the  present  time,  to  correlate  certain  of 
these  facts  with  familiar  pictures  of  disease,  and  to  apply  them  to 
medical  and  surgical  diagnosis.  The  purpose  has  been  to  inter- 
pret the  blood  report  according  to  its  true  value  as  a  clinical  sign, 
neither  exploiting  it  as  a  panacea  for  every  diagnostic  ill,  nor 
belittling  it  because  of  its  failure  consistently  to  give  the  sought- 
for  clue  in  every  instance. 

A  minimum  amount  of  theoretical  discussion  has  been  intro- 
duced in  the  sections  dealing  with  the  physiology  and  pathology 
of  the  whole  blood  and  of  the  cellular  elements — only  sufficient, 
in  the  author's  judgment,  to  add  clearness  to  a  number  of  the 
mooted  points  of  this  science,  which  in  its  present  transitional 
stage  must  still  be  regarded  as  one  from  which  more  or  less  hy- 
pothesis and  conjecture  are  inseparable.  Intimate  familiarity  with 
technique  being  an  essential  qualification  for  the  comprehensive 
study  of  the  blood,  a  somewhat  lengthy  consideration  of  this  sub- 
ject is  given.  The  methods  of  examination  likely  to  prove  useful 
in  every -day  practice  have  been  described  in  detail,  perhaps  some- 
times at  the  risk  of  prolixity,  in  the  hope  of  thus  simplifying  for 
the  novice  the  minutiae  of  blood  counting,  staining,  and  other 
means  of  investigation.  In  the  discussion  of  the  primaiy  anemias 
and  of  the  anemias  peculiar  to  infancy,  prominent  clinical  features 
other  than  those  referable  to  the  blood  have  been  briefly  men- 
tioned, in  order  to  add  clearness  to  the  differential  diagnosis.  For 
convenience  in  reference,  the  various  diseases  included  in  the  sec- 
tion on  general  hematology  are  arranged  alphabetically,  rather 
than  grouped  according  to  a  traditional  classification. 

The  greater  part  of  the  original  data  referred  to  in  the  text  is 
taken  from  the  records  of  the  Pathological  Institute  of  the  Ger- 
man Hospital,  where  a  systematic  account  of  all  blood  examina- 
tions has  been  kept  for  the  past  six  years.  The  remaining  data 
represent  the  writer's  personal  examinations  in  hospital  and  pri- 
vate practice  and  in  the  army  medical  service,  these  sources  of 
statistics  together  including  about  four  thousand  blood  reports  in 

various  pathological  conditions. 

vii 


VIU  PREFACE. 

Hematological  literature  has  been  freely  consulted  in  the  prep- 
aration of  this  volume,  special  acknowledgment  being  due  to 
Hayem,  Ehrlich  and  Lazarus,  von  Limbeck,  Rieder,  Lowit, 
Tiirk,  Grawitz,  Cabot,  Stengel,  Thayer,  Ewing,  Taylor,  and  Coles 
for  the  profitable  information  gleaned  from  their  writings.  Due 
credit  in  the  text  has  been  given  to  these  as  well  as  to  the  other 
authors  of  whose  labors  use  has  been  made. 

The  colored  plates  and  other  histological  illustrations,  the 
originals  of  which  were  made  by  Mr.  E.  F.  Faber  from  fresh  and 
stained  specimens,  bear  evidence  of  the  artist's  technical  skill  and 
faithful  attention  to  structural  detail.  ^Ir.  S.  Trenner  has  kindlv 
furnished  the  engravings  of  several  of  the  special  instruments. 

The  author  takes  pleasure  in  acknowledging  the  assistance  of 
his  wife  and  critic  in  revising  the  proof  of  these  pages ;  in  credit- 
ing Dr.  G.  P.  Miiller  for  collecting  and  verifying  much  statistical 
matter  relating  to  hospital  cases  ;  and  in  thanking  Dr.  J.  Chal- 
mers Da  Costa  and  Dr.  T.  G.  Ashton  for  helpful  suggestions. 

313  South  Thirteenth  Street,  Philadelphia, 
November,  1901. 


INTRODUCTION. 


The  rapid  growth  and  development  of  hematology  during  re- 
cent years  and  the  practical  application  of  many  of  its  teachings 
to  the  diagnosis  of  various  diseases  have  made  this  science  one 
which  no  progressive  medical  man  can  afford  to  disregard.  Ex- 
amination of  the  blood  gives  definite  clinical  information  which 
may  be  profitable  both  to  the  practitioner  of  internal  medicine 
and  to  the  surgeon,  and  the  procedure  is  capable  of  throwing 
light  upon  the  diagnosis  in  such  a  wide  range  of  pathological 
conditions  that  it  is  difficult  to  single  out  any  disease  in  which  it 
may  not  be  of  some  utility,  either  as  positive  or  as  negative  evi- 
dence. 

In  the  light  of  our  present  knowledge  of  the  subject,  clinical 
information  of  two  different  kinds  may  be  derived  from  hematol- 
ogy, namely,  findings  which  are  pathognomonic  of  certain  dis- 
eases ;  and  auxiliary  data  which,  if  considered  in  connection  with 
other  clinical  manifestations,  may  prove  either  essential  or  helpful 
in  establishing  the  precise  nature  of  a  disease. 

Pathognomonic  blood  findings  are  unfortunately  confined  to  a 
limited  number  of  diseases  :  leukemia,  the  malarial  fevers,  relaps- 
ing fever,  and  filariasis.  In  pernicious  anemia  a  typical  picture 
is  also  found,  if  two  conditions  capable  of  exciting  identical  blood 
changes  are  excepted,  the  profound  secondary  anemias  due  to 
certain  intestinal  parasites  and  to  nitrobenzol  poisoning. 

The  blood  examination  affords  data  which,  although  not  pa- 
thognomonic, are  nevertheless  essential  for  the  diagnosis  of  chlo- 
rosis, Hodgkin's  disease,  splenic  anemia,  and  secondary  ane- 
mias dependent  upon  various  causes.  For  example,  in  chlorosis 
a  definite  group  of  blood  changes  must  exist  in  order  to  justify 
an  unconditional  diagnosis,  although  the  occurrence  of  these 
changes,  unassociated  with  other  equally  definite  clinical  signs, 
is  insufficient  evidence  of  this  disease.  In  Hodgkin's  disease,  a 
condition  indistinguishable  from  leukemia  by  an  ordinary  phys- 
ical examination,  the  absence  of  a  leukemic  state  of  the  blood  at 
once  excludes  the  latter  disease.  In  the  secondary  anemias,  it  is 
obvious  that  the  blood  count  alone  can  give  the  exact  clue  to  the 
condition,  by  determining  the  degree  and  character  of  the  blood 
impoverishment,  and  by  tracing  from  time  to  time  its  progress. 


IX 


X  INTRODUCTION. 

In  this  connection  it  is  important  to  remember  that  pallor  may 
go  hand  in  hand  with  a  normal  hemoglobin  percentage  and  eryth- 
rocyte value,  and  that  on  the  other  hand  a  high  color  by  no 
means  invariably  signifies  that  the  individual  is  not  anemic.  In 
addition  to  the  diseases  just  named,  hematology'  gives  informa- 
tion which  is  often  of  great  assistance  in,  although  not  essential 
for,  the  diagnosis  of  such  conditions  as  enteric  fever,  sepsis, 
pneumonia,  appendicitis,  diabetes,  syphilis,  malignant  disease, 
trichiniasis,  and  suppurative  processes.  Clinical  experience  has 
repeatedly  illustrated  the  value  of  the  serum  reaction  in  typhoid 
and  in  Malta  fevers,  of  Williamson's  test  in  diabetes  mellitus,  of 
eosinophilia  in  trichiniasis,  and  of  leucocytosis  in  sepsis,  malignant 
neoplasms,  suppurative  lesions,  and  many  of  the  acute  infections. 

Negative  results  from  a  blood  examination  also  possess  diag- 
nostic value  within  certain  limits,  but  too  great  reliance  upon  evi- 
dence of  this  sort  more  often  proves  delusiv^e  than  helpful.  In  a 
patient  whose  waxy,  yellowish  facies  suggests  with  equal  force 
pernicious  anemia,  chronic  nephritis,  and,  perhaps,  liver  cirrhosis, 
the  absence  of  characteristic  blood  changes  is  sufficient  to  exclude 
the  first-named  condition.  But  failure  to  detect  the  malarial  para- 
site does  not  necessarily  exclude  malarial  fever ;  a  negative  serum 
test  does  not  absolutely  rule  out  enteric  fever;  and  an  absence  of 
leucocytosis  cannot  be  regarded  as  an  infallible  sign  that  a  sup- 
purative focus  does  not  exist,  nor  does  it  always  indicate  the 
benignity  of  a  neoplasm.  Negative  evidence,  then,  is  usually  to 
be  considered  merely  suggestive,  the  real  pertinence  of  the  hint 
thus  obtained  depending  upon  its  correlation  with  other  physical 
signs  and  symptoms. 

The  significance  of  positive  findings  in  bacteriological  investiga- 
tions of  the  blood  is  patent,  and  the  conclusive  value  of  this 
means  of  research  in  identifying  obscure  cases  of  general  sepsis, 
malignant  endocarditis,  enteric  fever,  and  plague,  has  been  demon- 
strated in  many  instances.  Thje  conflicting  and  indifferent  results 
which  some  investigators  hav^e  obtained  by  this  procedure  were 
doubtless  due  largely  to  faulty  technique,  but  these  results  promise 
to  become  more  dependable  and  certain  with  the  adoption  or 
more  exact  technical  methods. 

At  the  present  time  the  most  useful  information  furnished  by 
hematology'  has  been  derived  from  study  of  the  cellular  elements 
of  the  blood,  but  closer  familiarity  with  the  chemistry  of  this 
tissue,  still  an  undeveloped  science,  will  undoubtedly  in  the  near 
future  afford  not  only  more  tangible  clues  to  the  etiology  and 
pathology  of  the  blood  diseases,  but  also  will  bring  to  light  addi- 
tional facts  which  may  be  applied  to  the  diagnosis  of  these  and 


INTRODUCTION.  XI 

other  maladies.  The  study  of  the  coagulation  time  of  the  blood 
already  promises  to  be  of  practical  utility  in  the  diagnosis  and 
prognosis  of  cases  of  purpura,  hemophilia,  and  jaundice,  which 
are  characterized  by  slow  clotting  and  by  a  tendency  toward 
hemorrhage. 

The  technique  of  blood  examinations,  such  as  described  in 
the  following  pages,  is  neither  elaborate  nor  difficult  to  master. 
Necessarily,  it  must  be  rigidly  exact,  but  no  more  so  than  any 
other  branch  of  physical  diagnosis,  if  the  worker  is  content  only 
with  the  best  results.  To  acquire  a  good  working  knowledge  of 
hematology  takes  but  a  fraction  of  the  time  and  application  that 
one  must  spend  in  familiarizing  one's  self  with  the  most  com- 
mon heart  murmurs  or  chest  signs,  and  the  time  thus  spent 
equips  the  physician  with  an  additional  diagnostic  agent  of  the 
greatest  value.  If  the  newly-graduated  physician  would  provide 
himself  with  a  microscope  and  a  set  of  blood  instruments,  and 
systematically  study  the  blood  in  the  various  general  diseases 
which  he  encounters  in  practice,  many  a  slip-shod  diagnosis 
might  be  avoided,  and  a  great  stride  forward  made  in  popularizing 
this  practical  branch  of  clinical  diagnosis. 


TABLE   OF    CONTENTS. 


INTRODUCTION 


IX 


SECTION   I. 
EXAMINATION   OF  THE    BLOOD    BY    CLINICAL   METHODS. 

Page. 


General  Schema 


I. 


Hemoconia 


Hemoglobin 


Examination  of  the  Fresh  Blood 
Obtaining  the  Specimen 
Preparing  the  Shde 
Microscopical  Examination     . 
Changes  Affecting  the  Erythrocytes 
Changes  Affecting  the  Leucocytes  . 
Increase  of  Fibrin,  Blood  Plaques,  and 
Blood  Parasites      .  •  •         • 

Foreign  Bodies      .  •  •         • 

II.  Estimation  of  the  Percentage  of 

Von  Fleischl's  Hemometer 
Ohver's  Hemoglobinometer 
Gowers'  Hemoglobinometer 
Dare's  Hemoglobinometer 
Tallquist's  Method 

III.  Counting  the  Erythrocytes  and  the  Leucocytes 
Methods         .         •  •  • 
Diluting  Fluids 

The  Thoma-Zeiss  Hemocytometer 
Counting  the  Erythrocytes      • 
Counting  the  Leucocytes 
Cleaning  the  Pipette 
Durham's  Hemocytometer     • 
Gowers'  Hemocytometer 
Ohver's  Hemocytometer 

IV.  Microscopical  Examination  of  the  Stained  Specimen  , 
Objects  of  Staining 
The  Anihne  Dyes  . 
Preparing  the  Films 
Fixation  Methods  . 
Methods  of  Staining 
Ehrhch's  Triacid  Stain 
Jenner's  Stain 
Prince's  Stain 

xiii 


19 

19 

19 
21 

22 

22 

23 
24 
24 
24 

25 
25 
32 
34 
36 
39 

40 
40 
40 

42 

45 
49 
52 
52 
54 
56 

58 

58 

59 

59 
61 

63 
64 

65 
66 


XIV 


TABLE    OF  CONTENTS. 


Staining  with  Eosin  and  Methylene-blue 
Staining  with  Eosin  and  Hematoxyhn    . 
Staining  with  Thionin    .... 
Staining  with  Polychrome  Methylene-blue 
Differential  Counting      .... 

V.  Counting  the  Blood  Plaques    • 

Determann's  Method     .... 

VI.  Estimation  of  the  Relative  Volumes  of  Corpuscles  an 

Plasma     ...... 

Daland's  Hematocrit      .... 

Limitations  of  the  Hematocrit 

VII.  Estimation  of  the  Specific  Gravity 
Hammerschlag's  Method        .         •         . 

VIII.  Estimation  of  the  Alkalinity 
Engel's  Alkalimeter 

IX.  Determination  of  the  Rapidity  of  Coagulation 
Glass  Slide  Method 
Wright's  Coagulometer 

X.  Spectroscopical  Examination    . 

The  Sorby-Beck  Microspectroscope 

XI.  Bacteriological  Examination 
Value  of  Positive  Findings 
Methods         ..... 
Blood  Cultures       .  .  •         • 
Staining  Methods 

XII.  Determination  of  the  Serum  Reaction 
Widal'sTest  ...... 

The  Specific  Test  for  Human  Blood 


D 


Page. 
67 

68 
69 
69 
70 

71 

72 


72 

73 
74 

75 
75 

n 
77 

79 
80 
80 

81 
81 

83 
83 
83 
83 

85 

86 
86 
88 


SECTION   II. 
THE   BLOOD    AS   A   WHOLE. 


I.  General  Composition    . 

Plasma,  Serum,  and  Cells 
Salts      . 
Extractives 
Gases    . 

II.  Color   . 

Normal  Variations 
Density  and  Opacity 
Pathological  Variations 

III.  Odor  and  Viscosity 

IV.  Reaction 
Reaction  in  Health 


93 
93 
93 
94 
94 

94 
94 
94 
94 

95 

95 
95 


TABLE    OF   CONTENTS. 


XV 


Table  of  Normal  Blood  Alkalinity  . 

96 

Physiological  Variations          .          .          .          . 

96 

Pathological  Variations  .         .         .         .         . 

97 

V.  Specific  Gravity  ...... 

98 

Normal  Range        ..... 

98 

Pathological  Variations  .... 

99 

Relation  of  Specific  Gravity  to  Hemoglobin 

99 

Table  of  Hemoglobin  Equivalents  . 

100 

VI.  Fibrin  and  Coagulation     .        .        .        . 

100 

Relation  of  Fibrin  to  Coagulation 

100 

Appearance  of  Fibrin  in  Fresh  Blood 

lOI 

Hyperinosis  and  Hypinosis     . 

102 

Pathological  Variations  in  Amount  of  Fibrin  . 

102 

VII.  Oligemia    ....... 

103 

Definition       ...... 

103 

Occurrence    ...... 

103 

VIII.  Plethora  ...... 

104 

Definition       ...... 

104 

Permanent  and  Transient  Polyemia 

104 

Serous  Plethora      ..... 

104 

Cellular  Plethora    ..... 

105 

IX.   Hydremia    ...... 

105 

Definition       ...... 

105 

Causes  ....... 

105 

Occurrence    ...... 

105 

X.  Anhydremia 

106 

Definition       ...... 

106 

Causes  ....... 

106 

Occurrence    ...... 

106 

XI.    LiPEMIA          ...... 

106 

Amount  of  Fat  in  Normal  Blood      • 

106 

Definition       .          . 

107 

Physiological  and  Pathological  Lipemia  . 

107 

Tests  for  Fat           ..... 

107 

XII.   Melanemia 

107 

Definition       ...... 

107 

Occurrence     ...... 

108 

XIII.   Glycemia 

108 

Amount  of  Sugar  in  Normal  Blood 

108 

Hyperglycemia       ..... 

108 

Test  for  Sugar        ..... 

108 

XIV.  Uricacidemia 

109 

Definition       ...... 

109 

Occurrence    ...... 

109 

Test  for  Uric  Acid  ..... 

109 

XVI 


TABLE    OF  CONTENTS. 


XV.  Cholemia  .  .  .  .  . 
Definition  .  .  .  .  . 
Occurrence  .  .  .  .  . 
Test  for  Bile  .  .  .  . 

XVI.  Acetonemia  and  Lipacidemia 
Definition      .  .  .  .  • 
Occurrence              .          .          .  . 
Tests  for  Acetone  and  Fatty  Acids 

XVII.  Bacteriemia    . 
Occurrence 
Latent  Infection 
Blood  Cultures 
Bacteria  Found  in  the  Blood 


XVIII.  Anemia  . 
Definition 
Pseudo-anemia 
Classification 
Patho2"enesis 


Page, 

I  lO 

IIO 

IIO 

IIO 

IIO 

IIO 

IIO 

IIO 

III 

III 

III 

112 

112 

113 

113 

113 

114 

115 

SECTION  III. 

HEMOGLOBIN.   ERYTHROCYTES,   BLOOD  PLAQUES, 
AND    HEMOCONIA. 


II. 


III. 


Hemoglobin 

119 

General  Properties 

119 

Origin 

120 

Variations  in  Amount 

121 

Absolute  Amount 

122 

Color  Index 

122 

Hemoglobinemia 

123 

Methemoglobinemia 

124 

Carbon  Monoxide  Hemoglobin 

125 

Erythrocytes 

126 

Appearance  in  Fresh  Blood    . 

126 

Histological  Structure     . 

127 

Origin  and  Life  History- 

128 

Size 

Normal  Number     . 

129 
129 

Volume  Index 

130 

.  Influence  of  Physiological  Factors    0: 

S'     THE      ERYTH-  . 

rocytes             ..... 

130 

Age  and  Sex            ..... 
Pregnancy,  Menstruation,  and  Lactation 

130 
131 

Constitution  and  Nutrition 

132 

Fatigue 

Digestion  and  Food 

High  Altitudes 

• 

132 
132 
133 

TABLE    OF  CONTENTS. 


XVI 1 


IV.  Pathological  Changes  in  the 
Ameboid  Motility 
Alterations  in  Isotonicity 
Hyperviscosity 
Deformities  of  Shape  and  Size 

Megalocytes   . 

Microcytes 

Poikilocytes 
Endoglobular  Degeneration 
Total  Necrosis 
Atypical  Staining  Reactioi> 
Nucleation     . 

Normoblasts 

Megaloblasts 

Microblasts     . 

Atypical  Erythroblasts 
Granular  Degeneration 
Oligocythemia 
Polycythemia 

V.  Blood  Plaques 

Appearance  in  Fresh  Blood 

Histological  Structure    . 

Origin 

Normal  Number    . 

Pathological  Variations 

VI.  Hemoconia 
Appearance  in  Fresh  Blood 
Histological  Characteristics 
Occurrence    . 


Erythrocytes 


Page. 

135 
136 

136 
136 
137 
137 
138 

139 
140 

141 

141 

143 

145 
146 

147 
148 
149 


SECTION   IV. 


THE   LEUCOCYTES. 


General  Characteristics 
Appearance  in  Fresh  Blood 
Ameboid  Movement 
Cell  Granules 
Normal  Number    . 


H.  Classification 

Number  and  Percentage 
Small  Lymphocytes 
Large  Lymphocytes 
Transitional  Forms 
Polynuclear  Neutrophiles 
Eosinophiles 
Basophile  Cells 
Myelocytes    . 
Mast  Cells     . 
1* 


of  Different  Varieties 


»55 

155 

156 

157 
159 

159 

159 
160 

161 
162 
163 
165 
166 
167 
168 


XVlll 


TABLE    OF  CONTENTS. 


Mononuclear  Neutrophiles 

Neutrophilic  Pseudolymphocytes 

Reizungsformen     . 

Differential  Table  of  the  Leucocytes 

Origin  and  Development 

Iodine  Reaction     . 

Perinuclear  Basophilia   . 


toses 


III.  Leucocytosis 

Definition  .... 
Classification  of  the  Leucocyte 
Physiological  Leucocytosis 

Character 

Causal  Factors 

Leucocytosis  of  the  New-born 

Digestion  Leucocytosis 


Leucocytosis  of  Pregnancy  and  Parturition 
Leucocytosis  Due  to  Thermal  and  Mechanical 
Terminal  Leucocytosis     .... 
Pathological  Leucocytosis 
Occurrence 
Degree  of  Increase 
Differential  Changes 
Causal  Factors 

Functions        ..... 
Hypoleucocytosis  and  Hyperleucocytosis 
Inflammatory  and  Infectious  Leucocytosis 
Leucocytosis  of  Malignant  Disease 
Post-hemorrhagic  Leucocytosis 
Toxic  Leucocytosis 
Experimental  Leucocytosis 


IV.  Lymphocytosis     . 
Definition 

Differential  Changes 
Causal  Factors 
Physiological  Lymphocytosis 
Pathological  Lymphocytosis   . 
Experimental  Lymphocytosis 
Clinical  Significance 


EOSINOPHILIA  .... 

Definition       ..... 
Causal  Factors        .... 
Physiological  Eosinophilia 
Pathological  Eosinophilia 
Experimental  Eosinophilia 
Diminution  in  the  Number  of  Eosinophiles 
Clinical  Significance       .... 


Influences 


Pagb. 
171 
171 

171 
172 

173 
176 

176 
176 
177 
177 
177 
178 
178 
179 
180 
iBi 
181 
182 
182 
183 
183 
184 
184 
185 

187 
190 
191 
192 

193 

196 
196 
196 
197 
197 
197 
198 
198 

198 
198 
199 
199 
200 
201 
201 
201 


VI.  Basophilia  . 


202 


TABLE   OF  CONTENTS. 


XIX 


VII.  Myelemia  . 
Definition 
Occurrence    . 
Causal  Factors 

VIII.  Leucopenia 
Definition 

Differential  Changes 
Physiological  Leucopenia 
Pathological  Leucopenia 
Experimental  Leucopenia 


Page. 
202 
202 
202 
203 

203 
203 
204 
204 
205 
207 


SECTION   V. 

DISEASES  OF   THE    BLOOD. 

I.  Chlorosis       .... 

Appearance  of  the  Fresh  Blood 
Coagulation  .... 
Specific  Gravity 
Alkalinity      .... 
Hemoglobin  and  Erythrocytes 
Color  Index  .... 
Deformed  and  Nucleated  Cells 
Leucocytes    .... 
Differential  Changes 
Blood  Plaques 

Diagnosis       .... 
Clinical  Features    . 

II.  Pernicious  Anemia 

Appearance  of  the  Fresh  Blood 

Coagulation  .... 

Specific  Gravity     . 

Alkalinity      .... 

Hemoglobin  and  Erythrocytes 

Color  Index  .... 

The  Blood  During  Remissions 

Megalocytosis 

Poikilocytosis 

Prevalence  of  Megaloblasts    . 

Polychromatophila 

Granular  Basophilia 

Leucocytes    .... 

Differential  Changes 

Blood  Plaques 

Diagnosis      .... 

Clinical  Features   . 

Pernicious  Anemia  and  Severe  Secondary  Anemia 

Pernicious  Anemia  and  Chlorosis  . 

Pernicious  Anemia  and  Bothriocephalus  Anemia 

Pernicious  Anemia  and  Nitrobenzol  Poisoning 


209 
209 
209 
209 
219 
210 
210 
210 
213 
214 
215 
216 
216 

218 

2X8 

219 
219 
220 
220 
220 

221 
221 
223 
224 
225 
226 
227 
227 
228 
228 
229 
230 
230 
231 
231 


XX 


TABLE    OF  CONTENTS. 


III.  Splenic  Anemia. 
Appearance  of  the  Fresh  Blood 
Hemoglobin  and  Er>'throcytes 
Color  Index  . 

Deformed  and  Nucleated  Cell 
Leucocytes    . 
Blood  Plaques 
Diagnosis 
Clinical  Features    . 
Splenic  Anemia  and  Spleno-medullar)'  Leukemia 
Splenic  Anemia  and  Pernicious  Anemia 
Splenic  Anemia  and  Hodgkin's  Disease 
Splenic  Anemia  and  Splenic  Tumors 

IV.  Secondary  Anemia 
Appearance  of  the  Fresh  Blood 
Coagulation  . 
Specific  Gravity 
Alkalinity 

Hemoglobin  and  Erythrocytes 
Color  Index  . 

Deformed  and  Nucleated  Cell 
Leucocytes    . 
Differential  Changes 
Blood  Plaques 
Diagnosis 

V.  POST-HEMORRHAGIC    AnEMIA 

Etiology 

Immediate  Effects  of  Hemorrhage 
Secondary  Effects  of  Hemorrhage  . 
Degree  of  Blood  Loss  Compatible  with  Life 
Regeneration  of  the  Blood 

Differential  Table  ..... 

VI.  Leukemia     ...... 

Varieties        ...... 

Parasitology  ...... 

Spleno-medullar)-  Leukemia  . 

Appearance  of  the  Fresh  Blood 
Coagulation     ..... 

Alkalinity 

Specific  Gravity       .... 

Hemoglobin  and  Erj-throcytes 
Color  Index    ..... 

Relation  of  Erythrocyte  and  Leucocyte  Counts 

Nucleated  Cells 

Leucocytes      ...... 

Influence  of  Arsenic  on  the  Leucocyte  Count 
The  Blood  During  Remissions 
Differential  Changes         .... 

Blood  Plaques  ..... 


Page. 
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231 
231 
231 
232 
233 
233 
233 
234 
235 
235 
235 
235 

236 
236 
236 
236 
237 
237 
237 
238 
238 
238 
239 
239 

239 

239 
240 

240 

240 

241 

243 

244 
244 
244 
246 
246 
247 
247 
247 
247 
248 
248 
248 
250 
250 
251 
252 
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TABLE    OF  CONTENTS. 


XXI 


Lymphatic  Leukemia 

Appearance  of  the  Fresh  Blood 

Hemoglobin  and  Erythrocytes 

Color  Index    .         .  .         • 

Deformed  and  Nucleated  Cells 

Leucocytes      .... 

Differential  Changes 

Blood  Plaques 
Acute  Leukemia    .... 
Influence  of  Intercurrent  Infections 
Diagnosis       ....•• 
Spleno-meduUary  and  Lymphatic  Leukemia 
Leukemia  and  Pathological  Leucocytosis 
Leukemia  and  Lymphocytosis 
Leukemia  and  Hodgkin's  Disease  • 
Leukemia  and  Tumors  of  the  Spleen,  Kidney,  and  Pancreas 
Leukemia  and  Lymphatic  Hyperplasia    . 

VII.  Hodgkin's  Disease    .... 
Appearance  of  the  Fresh  Blood 
Alkalinity,  Specific  Gravity,  and  Coagulation 
Hemoglobin  and  Erythrocytes 
Color  Index  ....•• 
Nucleated  and  Deformed  Cells 
Leucocytes     ...••• 
Differential  Changes       .... 
Diagnosis       ....•• 
Clinical  Features    .  .         .         •         • 
Hodgkin's  Disease  and  Tuberculous  Adenitis 
Hodgkin's  Disease  and  Syphilitic  Adenitis 
Hodgkin's  Disease  and  Local  Lymphoma 
Hodgkin's  Disease  and  Lymphatic  Sarcoma  . 
Hodgkin's  Disease  and  Lymphatic  Carcinoma 

VIII.  The  Effect  on  the  Blood  of  Splenectomy 
Hemoglobin  and  Erythrocytes  .... 
Leucocytes     ....•••• 

Differential  Changes 

Factors  of  the  Blood  Changes  Following  Splenectomy 

Differential  Table  . 


Page. 
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256 
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257 
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260 
260 
261 
263 
264 
265 
265 
266 
266 
266 

267 
267 
267 
267 
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268 
269 
270 
271 
271 
271 
271 
272 

272 
272 
272 
274 
274 

275 


SECTION  VI. 
THE   ANEMIAS   OF   INFANCY   AND   CHILDHOOD 

I.  Characteristics  of  the  Blood  in  Children 

Fetal  Blood   . 
The  Blood  at  Birth 

II.  Anemia  in  Children 

Frequency     . 
General  Characteristics 


279 
279 
280 

282 
282 
283 


XXll 


TABLE    OF  CONTENTS. 


Page. 

Classification          . 283 

Primary  Anemia    .         .          •         • 
Pernicious  Anemia 

284 
284 

Leukemia        .... 

284 

Secondary  Aremia 

Mild  Anemia  .         .          ■         • 

287 
287 

Severe  Anemia 

287 

Anemias  with  Leucocytosis 

287 

Etiology  of  Secondary  Anemia 
Anemia  Due  to  Syphilis  . 

288 
288 

Anemia  Due  to  Rachitis  . 

288 

Anemia  Due  to  Tuberculosis  • 

289 

Anemia  Due  to  Gastro-intestinal  Diseases 

289 

Post-typhoid  Anemia        .... 
Anemia  Infantum  Pseudoleukemica 

289 
290 

Bacteriemia  in  Children 

• 

292 

SECTION  VII. 


GENERAL  HEMATOLOGY. 

I.  Abscess 

Coagulation,  Fibrin,  and  Iodine  Reaction 

Hemoglobin  and  Erythrocytes 

Factors  of  the  Anemia  in  Abscess 

Color  Index  ...... 

Grade  of  Anemia  in  Different  Forms  of  Abscess 

Cell  Deformity  and  Nucleation 

Leucocytes  ...... 

Relation  of  the  Leucocyte  Count  to  the  Local  Lesion 

Range  of  the  Leucocyte  Count  in  Different  Forms  of  Abscess 

Differential  Changes      ....... 

Diagnosis       ......... 

II.  Acromegaly 

III.  Actinomycosis 

IV.  Acute  Yellow  Atrophy  of  the  Liver 

V.  Addison's  Disease 

VI.  Anthrax 

VII.  Appendicitis       .         . 

Factors  of  the  Anemia  in  Appendicitis 

Grade  of  Anemia  in  Catarrhal  and  Suppurative  Cases 
Hemoglobin  and  Erythrocytes         .  .         •         •         • 

Cell  Deformity  and  Nucleation        ..... 

Leucocytes    ......... 

Range  of  the  Leucocyte  Count  in  Different  Forms  of  Appendi 
citis  ......... 

Differential  Changes       ....... 

Diagnosis       ......... 


295 

295 
295 
-95 
295 
296 
296 
296 
297 

297 
297 
297 

298 

298 
298 
299 

299 

300 
300 
300 
300 
301 
301 

302 
302 
^,02 


TABLE   OF  CONTENTS. 


XXlll 


Page. 

VIII.  Asiatic  Cholera 

304 

IX.  Asthma  and  Emphysema             

305 

X.  Bronchitis            . 

306 

XI.  Bubonic  Plague 

306 

Bacteriology           . 

306 

Serum  Reaction     . 

307 

Hemoglobin  and  Erythrocytes 

307 

Leucocytes              .          .          

307 

Blood  Plaques        . 

308 

XII.  Cholelithiasis 

308 

Fibrin  and  Coagulation 

308 

Bacteriology           . 

308 

308 

Leucocytes              ........ 

309 

Diagnosis      ......••• 

309 

XIII.  Diabetes  Mellitus 

309 

Alkalinity,  Lipemia,  Lipacidemia,  and  Glycemia  . 

309 

Williamson's  Test 

309 

Bremer's  Test        ..•••••• 

310 

Hemoglobin  and  Erythrocytes 

311 

Leucocytes 

312 

Digestion  Leucocytosis  ....... 

312 

Iodine  Reaction     . 

312 

Diagnosis       .....•••• 

312 

312 

Hemoglobin  and  Erythrocytes 

312 

Leucocytes     ...•••••• 

313 

Course  of  the  Leucocytosis      ...... 

314 

Influence  of  Antitoxin  on  the  Leucocyte  Count 

314 

Differential  Changes 

315 

Affinity  of  the  Leucocytes  for  Basic  Dyes 

315 

316 

XV.  Enteritis 

316 

Acute  Catarrhal,  Chronic  Ulcerative,  and  Phlegmonous 

316 

Gastro-enteritis      ........ 

.           316 

Dysentery 

.           316 

Effect  of  Saline  Purges 

.            316 

XVI.  Enteric  Fever 

317 

Bacteriology           ........ 

317 

Blood  Cultures       . 

317 

Spot  Cultures         . 

.           318 

Serum  Reaction     . 

319 

Hemoglobin  and  Erythrocytes 

326 

Cell  Deformity  and  Nucleation 

328 

Leucocytes 

328 

Differential  Changes       ....... 

330 

Effect  of  Complications 

330 

XXIV 


TABLE    OF  CONTENTS. 


Blood  Plaques 

Diagnosis       .... 

XVII.  Erysipelas 

XVIII.  Exophthalmic  Goitre  . 

XIX.  Fever        .... 
Factors  of  the  Blood  Changes 
Pyrexial  Polycythemia 
Post-febrile  Anemia 
Coagulation,  Fibrin,  and  Leucocytes 
Alkalinity      .... 

XX.  FiLARIASIS  .... 
Occurrence    .... 
Parasitology  .... 
The  Filaria  Nocturna 
Technique  of  Examination 
Staining  the  Filariae 
Hemoglobin  and  Erythrocytes 
Leucocytes    .... 
Diagnosis       .... 

XXI.  Fractures 

XXII.  Gastritis 
Acute  and  Chronic  Forms 
Hyperchlorhydria,  Hypochlorhydria,  Gastric 

Dilatation,  Gastric  Neurasthenia 
Diagnosis      .... 

XXIII.  Gastric  Ulcer 
Hemoglobin  and  Erythrocytes 
Effects  of  Hemorrhage  and  Emesis 
Leucocytes     . 
Diagnosis 

XXIV.  Glanders 

XXV.  Gonorrhea 

XXVI.  Gout 
Alkalinity  and  Fibrin 
Uric  Acid 
Cellular  Elements 
Perinuclear  Basophilia    . 

XXVII.  Hemorrhagic  Diseases 
Specific  Gravity     . 
Bacteriology 
Alkalinity 
Coagulation 

Hemoglobin  and  Erythrocytes 
Leucocytes    . 
Blood  Plaques 


Achyl 


ia.  Gastric 


Page. 

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332 

333 

333 
333 
333 
334 
334 
334 

334 
334 
335 
335 
340 

341 
341 
342 

342 

343 

343 
343 

344 

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346 

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347 
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TABLE    OF  CONTENTS. 


XXV 


XXVIII.  Hepatic  Cirrhosis 

Anemia  in  Atrophic  Cirrhosis         .... 

Effect  of  Ascites     .         .  ..... 

Anemia  in  Hypertrophic  Cirrhosis 

Leucocytes  in  Atrophic  and  Hypertrophic  Cirrhoses 

Diagnosis      ........ 

XXIX.  Herpes  Zoster 

XXX.  Icterus  . 

Fibrin,  Coagulation,  Specific  Gravity,  and  Alkalinity 
Hemoglobin  and  Erythrocytes         .... 

Leucocytes    ........ 

Diagnosis      ........ 

XXXI.  Influenza      . 

XXXII.  Insolation  . 

XXXIII.  Intestinal  Helminthiasis 
Factors  of  the  Blood  Changes  .... 
Hemoglobin  and  Erythrocytes  .... 
Bothriocephalus  Anemia  ..... 
The  Anemia  of  Ankylostomiasis  .... 
Leucocytes    .         .         .         .         • 

XXXIV.  Intestinal  Obstruction     .... 

XXXV.  Leprosy 

XXXVI.  Malarial  Fever 

Parasitology  ....... 

Developmental  Cycle  of  the  Malarial  Parasite  in  Man 
Developmental  Cycle  of  the  Malarial  Parasite  in  the  Mosquito 
Varieties  of  the  Malarial  Parasite 
The  Parasite  of  Tertian  Fever 

Infections  with  Single  and  Multiple  Groups 

Anticipation  of  the  Paroxysm 

Intracellular  Hyaline  Forms   • 

Intracellular  Pigmented  Forms 

Segmenting  Forms 

Extracellular  Pigmented  Forms 

Flagellate  Forms     . 

Degenerate  Forms  . 
The  Parasite  of  Quartan  Fever 

Infections  with  Single  and  Multiple  Groups 

Intracellular  Hyaline  Forms    • 

iQtracellular  Pigmented  Forms 

Segmenting  Forms 

Extracellular  Pigmented  Forms 

Flagellate  Forms    . 

Degenerate  Forms 
The  Parasite  of  Estivo-autumnal  Fever 

Irregularities  in  Time  of  Developmental  Cycle 

Disc-  and  Ring-shaped  Forms 


Page. 

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351 

352 

352 

353 

353 
353 
353 
354 
354 

3  54 

355 

356 
356 
356 
356 
357 
357 

357 

358 

359 

359 

359 
360 

361 

362 

362 

362 

362 

363 
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366 

367 
367 
367 
368 
368 

369 
370 

370 
370 
370 
370 
371 


XXVI 


TABLE    OF   CONTENTS. 


Page. 


Pigmented  Forms   .... 

Segmenting  Forms  ... 

Erythropyknosis      .... 

Spherical,  Ovoid,  and  Crescentic  Forms 

Flagellate  Forms     .... 

Degenerate  Forms 
Pigmented  Leucocytes  and  Phagocytosis 
Differential  Table  of  the  Malarial  Parasites 
Technique  of  Examination 
Hemoglobin  and  Erythrocytes 
Causes  of  Malarial  Anemias  . 
Anemia  in  the  Regularly  Intermittent  Fevers 
Anemia  in  Estivo-autumnal  Fever 
Anemia  in  Malarial  Cachexia 
Types  of  Post-malarial  Anemia 
Leucocytes     .... 
Differential  Changes 
Blood  Plaques  .  . 

Diagnosis       .  . 

XXXVn.  Malignant  Disease    . 
Carcinoma     .... 
Fibrin  and  Coagulation   • 
Specific  Gravity  and  Alkalinity 
Glycemia 
Parasitology    . 

Hemoglobin  and  Erythrocytes 
Color  Index     .... 
Regeneration  of  the  Blood  after  Operation 
The  Oligocythemia  and  Polycythemia  of  Gastric  Cance 
Deformed  and  Nucleated  Cells 
Leucocytes      .... 
Frequency  of  Cancer  Leucocytosis 
Causes  of  Cancer  Leucocytosis 

Range  of  the  Leucocytes  in  Different  Forms  of  Cane  er 
Digestion  Leucocytosis  in  Gastric  Cancer 
Differential  Changes 
Sarcoma         ..... 
General  Features  of  the  Blood 
Hemoglobin  and  Erythrocytes 
Leucocytes      .... 
Diagnosis        .... 

XXXVIII.  Malignant  Endocarditis 
Bacteriology  ..... 
Hemoglobin  and  Erythrocytes 
Leucocytes     . 
Diagnosis 

XXXIX.  Malta  Fever 
XL.  Measles 
XLI.  Meningitis 


TABLE    OF  CONTENTS. 


XXVll 


XLII.   Myxedema         . 

XLIII.  Nephritis        . 

Factors  of  the  Blood  Changes         .... 

Specific  Gravity,  Fibrin,  Coagulation,  and  Alkalinity 
Bacteriology  ........ 

Hemoglobin  and  Erythrocytes        .... 

Anemia  in  Acute  and  Chronic  Parenchymatous  Nephriti 
Polycythemia  ....... 

Anemia  in  Chronic  Interstitial  Nephritis 
Leucocytes    ........ 

Uremia  .         .  . 

Diagnosis      ........ 

XLIV.  Nervous  and  Mental  Diseases    . 

Neuritis,  Beri-beri,  Neuralgia,  and  Brain  Tumor    • 
Neurasthenia,  Hypochondriasis,  and  Hysteria 
General  Paresis,  Dementia,  Melancholia,  and  Mania 
Convulsions,  Apoplectiform  Attacks,  and  Acute  Delirium 
Epilepsy,  Chorea,  and  Tetany 

XLV.  Obesity     ..... 
XLVI.  Osteomalacia 
XLVII.  Pericardial  Effusion 
XLVIII.  Peritonitis 

XLIX.  Pertussis         .... 

L.  Pleurisy  ..... 
Serous  Pleurisy  .... 
Purulent  Pleurisy  .... 
Diagnosis      ..... 

LI.  Pneumonia  ..... 
General  Features  of  the  Blood 
Bacteriology  ..... 
Hemoglobin  and  Erythrocytes 
Leucocytes    ..... 
Relation  of  Leucocytosis  to  Intensity  of  Infection 
Frequency  and  Extent  of  Leucocytosis 
Effects  of  Antipyresis     . 
Differential  Changes 
Blood  Plaques        .... 
Diagnosis      ..... 

LI  I.  Poisoning 

LIII.  Rabies       ..... 

LIV.   Relapsing  Fever 

Parasitology  .  .  .  .  • 

Lowenthal's  Reaction    . 
Hemoglobin  and  Erythrocytes 
Leucocytes    ..... 
Diagnosis       ..... 


Page. 

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399 

399 

399 
400 

400 

400 

401 

401 

401 

401 

402 
402 
402 

403 
404 
405 

405 
406 
406 
467 

408 

409 
409 
410 
411 

411 
411 
411 
412 
413 
413 
413 
414 

415 
415 
415 

416 

417 

418 
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420 
421 
421 
421 


XXVlll 


TABLE    OF  CONTENTS. 


LV.   Rheumatic  Fever       .... 
Coagulation,  Fibrin,  and  Alkalinity 
Bacteriology  ..... 

Hemoglobin  and  Erythrocytes 
Leucocytes    ...••• 
Diagnosis      ...... 

LVI.  Scarlet  Fever  .... 

Coagulation,  Fibrin,  and  Specific  Gravity 
Bacteriology  ...... 

Hemoglobin  and  Er^'throcytes 
Leucocytes    ...... 

Blood  Plaques        ..... 

Diagnosis      ...... 

LVII.  Septicemia  and  Pyemia  . 
Factors  of  the  Blood  Changes 
Fibrin  ....... 

Serum  Reaction     ... 
Bacteriology  ...... 

Hemoglobin  and  Erythrocytes 

Color  Index  ...... 

Deformed  and  Nucleated  Cells 
Leucocytes    ...... 

Differential  Changes      .... 

Diagnosis       ...... 

LVIII.  Syphilis  ..... 

Hemoglobin  and  Erythrocytes 
Syphilitic  Chlorosis  and  Pernicious  Anemia 
Effect  of  Mercur}^  on  the  Blood 
Justus'  Test  . 
Leucocytes    . 
Diagnosis 

LIX.  Tetanus     . 

LX.  Tonsillitis 

LXI.  Trichiniasis 

LXII.  Tuberculosis  . 

General  Features  of  the  Blood 
Bacteriology 
Serum  Reaction 
Hemoglobin  and  Erythrocytes 
Anemia  in  Pulmonary  Tuberculosis 
Anemia  in  Bone  Tuberculosis 
Anemia  in  Tuberculous  Adenitis,  Meningitis, 
risy,  and  Peritonitis,  and  in  Genito-Urinar}' 
Leucocytes    ...... 

Differential  Changes       .... 

Iodine  Reaction     ..... 

Perinuclear  Basophilia    .... 

Range  of  the  Leucocytes  in  Pulmonary  Tuberculosis 


Pericarditis,  Pleu- 
Tuberculosis     • 


TABLE   OF  CONTENTS. 


XXIX 


Range  of  the  Leucocytes  in  Bone  Tuberculosis 

Range  of  the  Leucocytes  in  Acute  Miliary  Tuberculosis,  Tuber 

culous  Adenitis,  Pleurisy,  Peritonitis,  Pericarditis,  and  Men 

ingitis,  and  in  Genito-Urinary  Tuberculosis 
Effect  of  Secondary  Septic  Infections 
Diagnosis      .... 

LXIII.  Typhus  Fever 
Parasitology 

Hemoglobin  and  Erythrocytes 
Leucocytes  .... 
Diagnosis      .... 

LXIV.  Vaccination   . 

LXV.  Valvular  Heart  Disease 
Stage  of  Compensation  . 
Acute  Rupture  of  Compensation 
Effect  of  Stasis 

LXVL  Varicella 

LXVH.  Variola 

Fibrin  and  Parasitology 
Hemoglobin  and  Erythrocytes 
Leucocytes    .... 
Blood  Plaques 
Diagnosis      .... 

LXVni.  Yellow  Fever     . 
Fibrin  and  Coagulation 
Bacteriology 
Serum  Reaction     . 
Hemoglobin  and  Erythrocytes 
Degenerative  Changes 
Leucocytes    .... 
Differential  Changes 
Diagnosis      .... 


Page. 

441 


443 
443 
443 

444 

444 

444 
445 
445 

445 

446 
446 
446 
446 

447 

448 
448 
448 
448 
449 
449 

449 

449 
450 

450 

450 

451 
451 
451 
451 


LIST   OF    ILLUSTRATIONS. 


Plate. 

I.  The  Erythrocytes 

II.  The  Leucocytes 

III.  Leucocytosis 

IV.  Spleno-meduUary  Leukemia 
V.  Lymphatic  Leukemia 

VI.  The  Tertian  Malarial  Parasite 

VII.  The  Quartan  Malarial  Parasite 

VIII.  The  Estivo-autumnal  Malarial  Parasite 


Page. 

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154 
176 
246 
256 
362 
366 
371 


Chart. 

I.   Pernicious  Anemia        ..... 
II.   Spleno-medullary  Leukemia 
III.   Multiple  Infections  in  Malarial  Fever    . 

Figure. 

1.  Blood  Lancet         ...... 

2.  Proper  Distribution  of  Cells  in  a  Blood  Film  . 

3.  Von  Fleischl's  Hemometer    .... 

4.  Tinted  Wedge  of  von  Fleischl's  Hemometer 

5.  Capillary  Pipette  of  von  Fleischl's  Hemometer 

6.  Method  of  using  the  von  Fleischl  Hemometer 

7.  Light-proof  Box  for  von  Fleischl's  Hemometer 

8.  Method  of  Using  Oliver's  Hemoglobinometer 

9.  Gower's  Hemoglobinometer  .... 

10.  Dare's  Hemoglobinometer     .... 

11.  Horizontal  Section  of  Dare's  Hemoglobinometer 

12.  Method  of  Filling  Blood  Chamber 

13.  Thoma-Zeiss  Hemocytometer 

14.  Thoma-Zeiss  Counting  Chamber    . 

15.  Ruled  Area  of  Thoma-Zeiss  Counting  Chamber 

16.  Ruled  Area  of  Zappert's  Counting  Chamber  . 

17.  Method  of  Filling  the  Hemocytometer    . 

18.  Plan  of  Counting  the  Erythroc)tes 

19.  Ocular  Diaphragm  ..... 

20.  Expelling  Contents  of  the  Erythrocytometer   . 

21.  Cross  Section  of  Durham's  Blood  Pipette 

22.  Method  of  Using  Oliver's  Hemocytometer 

23.  Superimposing  the  charged  Cover-glass 

24.  Drawing  Apart  the  Cover-glasses 

25.  The  Cover-glasses  after  Separation 

26.  Oven  for  Fixing  Blood-films 


222 
250 
361 


20 
21 
26 
26 
26 
29 
30 
33 
35 
36 
37 
38 
42 

43 
44 
44 

45 
48 

50 

52 

53 

57 

59 
60 

60 

61 


xxx 


LIST    OF    ILLUSTRATIONS. 


XXXI 


KlGUKK. 

27.  Daland's  Hematocrit     . 

28.  Engel's  Alkalimeter 

29.  Wright's  Coagulometer 

30.  Sorby-Beck  Microspectroscope 

31.  Sorby  Tubular  Cell 

32.  Needle  and  Tube  for  Aspirating  Blood  , 

33.  Rouleaux  Formation  and  Fibrin  in  Normal  Blood 

34.  Hyperinosis  ...... 

35.  Blood  Spectra       ...... 

36.  Degenerative  Changes  in  the  Erythrocytes 

37.  Changes  in  the  Erythrocytes  in  Chlorosis 

38.  Changes  in  the  Erythrocytes  in  Pernicious  Anemia 

39.  Atypical  Myelocytes  in  Spleno-medullary  Leukemia 

40.  Atypical  Polynuclear  Neutrophils  in  Spleno-medullary 

41.  Atypical  Lymphocytes  in  Lymphatic  Leukemia 

42.  Positive  Serum  Reaction  in  Enteric  Fever 

43.  Pseudo-reaction  in  Enteric  Fever  .... 

44.  Bacillus  Typhi  Abdominalis  .... 

45.  Filaria  Nocturna  in  Fresh  Blood    .... 

46.  Filaria  Nocturna,  showing  Granular  Degeneration 

47.  Filaria  Nocturna,  showing  Changes  in  Shape 

48.  Spirilla  of  Relapsing  Fever    ..... 


Leukemia 


Page. 

73 
78 
80 
81 
82 
84 

lOI 

102 
125 

139 
210 

221 

253 

254 

259 

319 
320 

321 
336 
338 
340 
418 


"  V avenir  appa^-tient  a  V  hematologie.  C'  est  elle  qui  nous  apportera  la 
solution  des  grands  problemes  nosologiques.  Elle  doit  nous  apparai'.re  com  me 
line  vaste  science  puisant  ses  viateriaux  dans  toutes  les  branches  des  connais- 
sanccs  biologiques  et  recueillant  les  diverses  notions  de  P hj(f/ioristne  ancien 
pour  les  rajeunir  et  les  completer  a  la  lumiere  des  decouvertes  modernes  en 
anatomic,  en  physiologic,  en  chimie  hiologique  et  en  pathologies 

Georges  Hayem. 


xxxii 


SECTION    I. 


EXAMINATION   OF    THE   BLOOD    BY   CLINICAL 

METHODS. 


SECTION   I. 


EXAMINATION    OF  THE    BLOOD    BY  CLINICAL 

METHODS. 

P  A   systematic  examination    of  the    blood  by 

^  clinical   methods  of  established  utility   includes 

the  following  twelve  different  processes  : 
I.    Microscopical  examination  of  the  fresh  blood. 
II.    Estimation  of  the  percentage  of  hemoglobin. 

III.  Counting  the  erythrocytes  and  the  leucocytes. 

IV.  Microscopical  examination  of  the  stained  specimen. 
These  four  procedures,  which  invariably  should  be  included  in 

every  clinical  blood-report,  furnish  the  most  important  informa- 
tion to  be  derived  from  hematological  study,  and  are  sufficient 
for  routine  clinical  work.     In  certain  instances  in  which  more  de- 
tailed investigation  of  special  points  is  sought,  it  may  be  thought 
advisable  to  supplement  the  above  plan   by  employing  one  or 
more  of  these  remaining  eight  procedures  : 
V.    Counting  the  blood-plaques. 
VI.    Estimation  of  the  relative  volumes  of  corpuscles  and 
plasma. 
VII.    Estimation  of  the  specific  gravity. 
VIII.    Estimation  of  the  alkalinity. 
IX.    Determination  of  the  rapidity  of  coagulation. 

X.    Spectroscopical  examination. 
XI.    Bacteriological  examination. 
XII.    Determination  of  the  serum-reaction. 

I.     EXAMINATION   OF   THE    FRESH    BLOOD. 

The  finger-tip  or  the  lobe  of  the  ear  is  the  part 
Obtaining      usually  selected  from  which  to  obtain  the  blood, 
THE  by  puncture,  for  examination.     The  former  site 

Specimen.       is  preferable  in  most  instances,  owing  to  its  con- 
venient situation  and  ease  of  manipulation  ;  but 
in  nervous  individuals  and  in  children  the  ear-lobe  may  be  chosen, 
because  of  its  limited  sensibility,  and  on  account  of  the  patient's 
inability  to  watch  the  operation. 


20         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

The  puncture  may  be  made  with  one  of  the  special  blood- 
lancets  devised  for  this  purpose,  or,  in  lieu  of  such  an  instrument, 
a  Hagedom  or  spear-pointed  surgical  needle,  or  a  new  sharp- 
pointed  steel  pen  from  which  one  prong  has  been  twisted  off,  will 
answer  the  purpose  equally  as  well.  The  author  is  accustomed 
to  use  a  small  steel  trocar-blade,  mounted  on  a  metal  shaft  which 
screws  into  an  outer  barrel,  by  means  of  a  thread.  By  the  use 
of  a  threaded  locking-nut,  any  desired  length  of  the  trocar  may 
be  exposed,  so  that  the  depth  of  the  wound  may  be  controlled 
at  will,  irrespective  of  the  force  used  to  drive  the  point  of  the 
P-j^    J  instrument  through  the  skin.     It  is  not 

necessary  to    steriHze    the    puncture- 


i::rJpj51jBiil       )    "^^<^^^  5    wiping  it   with   a   towel   wet 
with   alcohol  is    all  that  is  required. 


Blood-lancet.  .  ,.  .         ,  ^-.- 

in  ordinar^^  examinations.  Of  course, 
should  the  patient  happen  to  be  a  syphilitic,  it  is  safer  to  pass  the 
blade  through  an  alcohol  flame,  after  having  used  it. 

Having  chosen,  say,  the  patient's  middle  or  nng-finger,  the 
part  is  first  thoroughly  cleansed  with  alcohol  or  ether  and  then 
with  water,  and  wiped  perfectly  dry  with  a  clean,  lint-free  towel, 
which  may  be  then  folded  into  a  pad  and  slipped  behind  the  fin- 
ger to  isolate  it  from  the  neighboring  digits,  and  to  serve  as  a 
cushion  for  the  back  of  the  hand.  The  operator,  holding  the 
patient's  hand  in  a  firm,  steady  position,  makes  the  puncture  with 
a  rapid  motion  of  the  wrist,  such  as  one  is  accustomed  to  use  in 
percussing  the  thorax,  the  depth  of  the  wound  being  just  suffi- 
cient to  cause  a  free  flow  of  blood  in  good-sized  drops,  unaided  by 
the  slightest  pressure  on  the  finger  other  than  that  necessary  to 
start  the  initial  oozing.  The  needle  should  be  aimed  so  as  to 
strike  a  point  in  the  center  of  the  flexor  surface  of  the  finger,  just 
back  of  the  extreme  tip.  The  blood-drop  to  be  used  for  the  ex- 
amination should  under  no  circumstance  be  squeezed  from  the 
finger,  for  blood  secured  in  this  manner  is  certain  to  be  more  or 
less  highly  diluted  with  lymph  from  the  surrounding  tissues — a 
condition  which  will  give  rise  to  erroneous  results,  especially  to 
lower  hemoglobin,  specific  gravity,  and  corpuscular  estimations 
than  actually  exist.  In  severe  anemias,  especially  in  those  of 
the  pernicious  type,  the  bloodless  condition  of  the  superficial  ves- 
sels is  sometimes  so  marked  that  it  may  be  impossible  to  obtain 
enough  blood  for  the  examination  by  an  ordinary  puncture,  even 
from  the  ear-lobe,  which  as  a  rule  is  highly  vascular.  Relatively 
deep  incisions  are  unavoidable  in  such  instances.  On  the  con- 
trary in  most  cases  of  leukemia,  unless  the  coexisting  anemia 
is  of  striking  intensity,  the  blood  ^usually  flows  very  freely,  and 


EXAMINATION  OF  THE  FRESH  BLOOD. 


21 


may  even  spurt  from  the  wound  in  a  fine  jet  several  inches  in 
height. 

Most  writers  on  hematology  utter  an  emphatic  warning  against 
hemophilics,  in  whom  the  slightest  prick  of  a  needle  may  cause 
troublesome  bleeding.  The  writer  has  never  had  the  misfortune 
to^meet  with  this  accident,  but  recognizes  the  wisdom  of  observ- 
ing the  precaution  habitually  to  question  every  patient  concerning 
an  abnormal  tendency  toward  hemorrhage. 

The  observer's  attention  should  be  directed  to  the  color  and 
the  density  of  the  blood  drop  as  it  flows  from  the  puncture,  and 
a  note  taken  of  the  various  macroscopical  changes  which  may  oc- 
cur, such  as  the  pale,  hydremic  condition  of  the  blood  found  in 
severe  anemias,  and  the  milky  appearance  of  the  drop  in  leu- 
kemia and  in  diabetes.  These  and  other  alterations  in  the  naked- 
eye  appearance  of  the  fresh  blood  drop  have  been  discussed  in 
another  section. 

The  first  few  drops  of  blood  which  follow  the 

Preparing      puncture  are  wiped  away,  and  the  site  of  the  in- 
THE  cision  freed  from  every  trace  of  moisture,  after 

Slide.         which  a  perfectly  clean  cover-glass,  held  edge- 
wise between  the  thumb  and  forefinger,  is  lightly 
touched  to  the  sinnmit  of  the  next  drop  as  it  oozes  from  the 
puncture,  and  is  then  immediately  placed,  blood  side  downward, 

Fig.  2. 


@%   o 


Proper  distribution  of  the  corpuscles  in  a  fresh  blood-film  prepared  for 

MICROSCOPICAL   examination. 

upon  the  surface  of  a  clean  glass  slide.      If  the  cover-glass  and 
the  slide  are  perfectly  clean  and  dry,  and  if  the  drop  is  of  the 


22  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

proper  size,  the  blood  will  at  once  spread  out  in  a  thin  film  con- 
sisting of  a  single  layer  of  corpuscles.  (Fig.  2.)  Gently  heat- 
ing the  slide  over  an  alcohol  flame  just  before  use  will  ensure  a 
thin,  even  spread.  If  prolonged  study  of  the  specimen  is  intended, 
it  may  be  advisable  to  exclude  air  from  the  film,  by  ringing  the 
margins  of  the  cover-glass  with  a  thin  layer  of  cedar-oil,  or  of 
vaseline,  but  ordinarily  this  precaution  is  unnecessary.  In  order 
to  prevent  distortion  of  the  corpuscles,  pressure  must  be  avoided 
while  adjusting  the  cover-glass.  If  the  blood  does  not  spread  of 
itself,  without  the  aid  of  pressure,  it  is  usually  owing  to  the  pres- 
ence of  particles  of  dust  or  grease  between  the  opposed  surfaces 
of  the  slide  and  cover-glass. 

Absolute  cleanliness  of  the  covers  and  slides  is  an  essential 
detail  to  which  too  great  attention  cannot  be  paid,  for  neglect  of 
this  precaution  is  responsible  for  the  majority  of  failures  to  secure 
good  specimens.  Perhaps  the  most  useful  cleansing  agent  is  the 
solution  popularly  known  as  "  acid  alcohol  "  (hydrochloric  acid, 
I  part ;  absolute  alcohol,  29  parts  ;  water,  70  parts),  which 
quickly  and  effectually  removes  all  traces  of  grease  and  dirt  from 
the  glasses,  so  that  their  preliminar}^  soaking  in  soap-suds  or  in 
a  strong  mineral  acid,  as  some  recommend,  may  be  dispensed 
with.  The  slides  and  covers  may  be  conveniently  kept  in  closed 
glass  receptacles  containing  this  solution,  from  which  they  are 
removed  as  the  occasion  demands,  being  then  dried  and  polished 
with  a  bit  of  clean  linen,  or  with  tissue-paper.  Ordinary  soft 
"toilet-paper"  is  excellent  for  this  purpose.  Oblong  cover- 
glasses,  measuring  J  x  i-J  inches  and  of  **  No.  i  "  thickness,  are 
more  easily  handled  without  forceps  than  smaller  square  or  cir- 
cular slips,  and  also  have  a  much  larger  surface  than  the  latter, 
which  is  often  decidedly  advantageous. 

The  use  of  forceps  is  unnecessar)^,  if  care  is  observed  to  hold 
the  cov^er-glass  in  the  manner  already  directed,  so  that  only  its 
edges  come  in  contact  with  the  thumb  and  finger. 

The  specimen,  prepared  in  the  manner  just 
Microscopical  described,  is  examined  under  the  microscope 
Examination,  with  both  low  and  high  powers,  a  i  or  J  inch 
dr>',  and  a  ^^2  '^^h  oil-immersion  objective  being 
the  most  satisfactory  lenses  for  the  purpose.  The  substage.  con- 
denser and  diaphragm  should  be  adjusted  so  that  the  field  is  but 
moderately  illuminated,  rather  than  flooded  with  a  glare  of  white 
light.  Microscopical  examination  of  the  fresh  blood-film  fur- 
nishes information  about  the  following  points  : 

Changes  Affecting  the  ErytJirocytes.  With  a  little  practice,  one 
soon  becomes  able  to  detect  with  a  tolerable  degree  of  accuracy 


EXAMINATION  OF  THE  FRESH  BLOOD.  23 

any  conspicuous  decrease  in  the  number  of  erythrocytes,  by  the 
relatively  small  number  of  cells  in  the  field  in  comparison  with 
their  number  in  a  similar  field  of  normal  blood.  With  less  con- 
fidence, it  is  also  possible  to  decide  whether  or  not  the  number 
of  erythrocytes  is  much  in  excess  of  the  normal  standard. 

Deficiency  in  hemoglobin  produces  unmistakable  changes  in 
the  appearance  of  the  cells,  those  in  which  this  change  is  well- 
defined  appearing  as  pale,  washed-out  bodies  which  stand  in 
striking  contrast  to  the  darker,  yellowish-green  color  of  the  nor- 
mal erythrocytes. 

Abnormal  viscosity  of  the  erythrocytes,  their  tendency  towards 
rouleaux  formation,  the  presence  of  deformities  of  size  and  of 
shape,  and  the  occurrence  of  structural  degenerative  changes 
may  also  be  distinguished  in  the  fresh,  unstained  blood-film. 
Nucleated  erythrocytes  are  not  demonstrable  in  the  fresh  speci- 
men. 

Changes  Affecting  the  Leucocytes.  A  glance  is  usually  suffi- 
cient to  determine  whether  or  not  the  number  of  leucocytes  is 
markedly  in  excess  of  normal,  but  too  great  dependence  should  not 
be  placed  on  such  a  method  of  detecting  the  presence  or  absence 
of  a  leucocyte -increase,  since  it  is  at  the  best  approximate,  and 
sometimes  erroneous.  As  will  be  explained  elsewhere,  any 
marked  decrease  in  the  number  of  erythrocytes,  the  leucocytes 
remaining  normal,  may  so  increase  the  ratio  of  the  latter  to  the 
former,  that  the  leucocytes  may  be  apparently  increased. 

Having  tentatively  determined  that  an  increase  in  the  total 
number  of  leucocytes  is  present,  it  is  furthermore  possible  for 
one  familiar  with  the  morphology  of  the  unstained  leucocyte  to 
make  a  fairly  accurate  differential  count  of  these  cells,  and  thus 
to  decide  whether  the  increase  is  due  to  a  pure  leucocytosis,  or 
to  some  form  of  leukemia.  This  distinction  is  not  at  all  diffi- 
cult in  most  instances,  when  one  recalls  the  characteristics  of  the 
several  forms  of  leucocytes  in  the  fresh  blood-film,  viz.:  small 
lymphocytes,  large  lymphocytes,  and  transitional  forms,  appear- 
ing as  cells  having  a  single,  spherical,  or  indented  nucleus,  and  a 
clear,  shining,  non-granular  protoplasm;  polynuclearneutrophiles, 
as  cells  with  polymorphous  or  multiple  nuclei,  and  a  protoplasm 
crowded  with  very  fine,  moderately  refractive  granules  ;  eosino- 
philes,  as  cells  with  a  single,  polymorphous  nucleus,  or  multiple 
nuclei,  and  a  protoplasm  containing  coarse,  spherical,  highly  refrac- 
tive, fat-like  granules ;  and  myelocytes  as  cells  with  a  single 
spherical  or  ovoid  nucleus,  and  a  protoplasm  crowded  with  very 
fine,  moderately  refractive  granules.  It  is,  of  course,  obviously 
impossible  to  distinguish  basophile  cells  in  the  fresh  blood,   as 


24  EXAMINATION     OF    THE    BLOOD    BV    CLINICAL    METHODS. 

well  as  some  of  the  cells  containing  fine  eosinophile  granules, 
but  the  characteristics  noted  above  are  sufficiently  plain  to  justify 
at  least  a  provisional  diagnosis  of  either  of  the  conditions  in  ques- 
tion, which,  in  ever}'  instance,  should  be  verified  by  a  careful  ex- 
amination of  the  stained  specimen. 

While  most  of  the  degenerative  changes  which  affect  the  leuco- 
cytes are  clearly  demonstrable  only  in  the  stained  specimen,  it  is 
still  possible  to  recognize  some  of  the  grosser  examples  of  such  a 
process  by  a  study  of  the  fresh  film.  Vacuolation  of  both  nucleus 
and  protoplasm,  extrusion  of  portions  of  the  cell-substance,  and 
the  various  stages  of  nuclear  disintegration  and  of  apparent  solu- 
tion of  the  protoplasm  are  the  alterations  most  commonly  ob- 
served. In  certain  specimens  "fractured"  leucocytes  are  seen 
with  more  or  less  frequency,  a  cell  thus  affected  being  drawn  out 
into  a  diffuse,  irregularly  shaped  body  with  indistinct  and  ragged 
margins,  about  which  the  cell-granules,  which  have  escaped  from 
the  protoplasm,  are  scattered  in  the  form  of  a  nebulous  mass. 
The  eosinophile  leucocytes  seem  especially  prone  to  undergo 
this  disintegration.  The  exact  significance  of  this  phenomenon 
is  not  clear,  but  it  probably  represents  a  degenerative  change  in 
which  the  cells  have  become  abnormally  vulnerable,  and  thus 
highly  susceptible  to  mechanical  injury  from  the  pressure  of  the 
cover-glass. 

Ameboid  activity  of  the  leucocytes,  and  pigmentation  of  these 
cells  are  among  the  other  changes  to  be  obser\'ed  in  a  histolog- 
ical examination  of  the  unstained  blood-film. 

Increase  in  Fibrin,  Blood-Plaques,  and  Hemoconia.  The  den- 
sity of  the  fibrin  network  and  the  rapidit}'  with  which  it  forms 
may  be  studied  as  coagulation  of  the  blood-film  progresses. 
Unless  the  blood-plaques  are  ver}'  greatly  increased  in  number, 
they  are  not  usually  noticeable  in  the  specimen  prepared  in  the 
ordinaiy  mannef-.  The  presence  of  hemoconia  or  *'  blood- 
dust"  is  at  once  rendered  conspicuous  by  the  rapid  and  incessant 
molecular  motion  with  which  these  bodies  are  endowed. 

Blood  Parasites.  The  hematozoa  of  the  malarial  fevers,  the 
spirilla  of  relapsing  fever,  and  the  embr\'onic  forms  of  the  para- 
site of  filarial  disease  should  be  studied  in  the  fresh  blood  when- 
ever this  is  possible,  rather  than  in  the  fixed  and  stained,  film, 
since  in  the  latter  the  characteristic  morphology^  of  these  parasites 
is  greatly  altered,  and  their  motility  lost. 

Foreign  Bodies,  such  as  free  fat-droplets,  collections  of  extra- 
cellular pigment,  and,  very  rarely,  the  crystalline  bodies  of 
Charcot  may  also  be  obser\^ed  in  the  fresh  specimen,  during  the 
course  of  certain  diseases. 


ESTIMATION    OF    THE    PERCENTAGE    OF    HEMOGLOBIN.  25 

Microscopical  examination  of  the  fresh  specimen  should  form 
the  initial  step  taken  in  every  systematic  examination  of  the 
blood,  since  it  may  be  the  means  of  determining  whether  or  not 
a  more  elaborate  investigation  is  necessary.  By  this  simple  pro- 
cedure an  immediate  diagnosis  may  be  made  in  a  number  of  in- 
stances, while  in  others  the  findings,  although  not  pathogno- 
monic, are  of  distinct  clinical  value.  Close  familiarity  with  the 
normal  histology  of  the  blood  is,  of  course,  essential  for  the  ap- 
preciation of  the  various  pathological  changes  which  have  been 
outlined  above.  Fuller  reference  to  these  changes  has  been 
made  in  other  parts  of  this  book.     (See  Sections  III  and  IV.) 


II.     ESTIMATION   OF   THE    PERCENTAGE    OF    HEMO- 
GLOBIN. 

No  less  than  half-a-dozen  different  hemoglo- 
Methods.  binometers,  or  instruments  for  estimating  the 
amount  of  hemoglobin  in  the  blood,  are  in  vogue 
at  the  present  time,  of  which  the  most  reliable  for  general 
clinical  use  are  the  instruments  devised  by  von  Fleischl,  by 
Oliver,  and  by  Cowers.  The  hemometer  of  von  Fleischl  has 
been  the  general  favorite  for  a  number  of  years,  both  in  this 
country  and  on  the  Continent,  but  in  England  it  has  been  sup- 
planted to  some  extent,  first  by  Gowers'  hemoglobinometer,  and 
in  recent  years  by  the  hemoglobinometer  lately  invented  by 
Oliver.  All  three  instruments  are  based  upon  a  similar  principle, 
that  of  measuring  the  depth  of  color  of  the  diluted  blood  by  a 
standard  color-scale  of  varying  intensity,  the  gradations  of  which 
correspond  to  different  hemoglobin  values. 

With  this  instrument,  which  is  the  one  pre- 
VON  ferred  by  the  great  majority  of  clinicians,  the  color 

Fleischl's      of  a  fixed  volume  of  blood  in  an  aqueous  solu- 
Hemometer.    tion  of  a  definite  strength  is  compared  with  the 
color  of  a  movable  glass  wedge,  tinted  with  Cas- 
sius'   ''golden  purple."     The  hemometer  consists  of  the  follow- 
ing parts : 

(i)  A  tinted  glass  wedge,  the  thickest  portion  of  which  is  of  a 
deep  pink  color,  and  the  thinnest  portion  almost  colorless,  with 
every  intermediate  color  gradation  between  the  two  extremes. 
It  is  mounted  in  a  metal  frame  provided  with  a  scale,  graduated 
at  every  five  degrees  from  o  to  1 20,  the  former  corresponding  to 
the  thinnest,  and  the  latter  to  the  thickest  part  of  the  wedge. 
The  metal  frame  is  grooved  so  that  it  fits  beneath  (2)  a  small 


26 


EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 


Stage,  in  which  it  may  be  moved  backward  and  forward  by  turn- 
ing a  milled  wheel.  In  the  center  of  this  stage  there  is  a  circu- 
lar opening  through  which  the  light  of  a  candle  is  reflected  by  a 
disc  of  calcium   sulphate,  mounted  on  the  pillar  supporting  the 

stage,  like  the  mirror  of  a  micro- 
scope. Back  of  this  opening  there 
is  a  small  oval  slot  through  which 
the  scale  of  the  underlying  tinted 
wedge  is  visible,  when  the  latter 
is  adjusted  to  the  stage.  (3)  A 
mixing  chamber,  consisting  of  a 
short  metal  tube  closed  at  the  bot- 
tom by  a  disc  of  glass  and  divided 
into  two  equal  compartments  by  a 
vertical  partition,  fits  accurately 
over  the  circular  opening  in  the 
stage.  When  properly  adjusted  to 
the  latter,  the  vertical  partition 
exactly  coincides  with  the  upper 
edge  of  the  underlying  tinted  wedge,  so  that  the  upper  com- 
partment of  the  chamber  is  illuminated  by  the  dull  white  light 
from  the  reflector,  while  the  lower  compartment  receives  the 
color  of  the  tinted  wedere.      (4)  A  capillary  pipette  mounted  in  a 


Von  Fleischi- 


FlG.    4. 


Tinted  glass  wedge  of  the  von  Fleischl 
hemometek. 


short  metal  handle,  used  for 
making  the  blood  dilution. 
A  single  pipetteful  of  nor- 
mal blood  mixed  with  suffi- 
cient distilled  water  to  fill 
exactly  one  of  the  compart- 
ments of  the  mixing  cham- 
ber gives  a  solution  which 
matches  the  color  of  the 
tinted  wedge  opposite  the  mark  100.  (S)  A  small  fine-pointed 
glass  dropper,  used  for  filling  with  w-ater  the  compartments. 

Method  of  Use.  As  a  preliminary  step,  each 
compartment  of  the  mixing  chamber  is  filled 
about  one-quarter  full  of  distilled  water,  by 
means  of  the  glass  dropper  to  one  end  of  which  a 
rubber  cap  has  been  fitted.  A  puncture  having 
been  made,  as  previously  directed,  a  measured 
volume  of  blood  is  collected  by  bringing  one  end  of  the 
capillary  pipette  lightly  in  contact  with  the  blood  drop,  as  it 
oozes  from  the  wound,  so  that  the  tube  is  instantly  filled  with 
blood,   by   capillary  force.      No   difficulty   will   be  experienced 


Fig.  5. 

Capillary  pipette 

OF  VON  FlEISCHl's 
HEMOMETEK. 


ESTIMATION    OF    THE    PERCENTAGE    OF    HEMOGLOBIN.  2/ 

in  quickly  filling  the  tube  if  it  is  applied  horizontally  to  the 
side  of  the  blood  drop,  rather  than  vertically  to  its  summit, 
care  being  observed  not  to  immerse  the  end  too  deeply.  It 
is  needless  to  add  that  the  interior  of  the  tube  must  be  abso- 
lutely clean  and  dry,  to  insure  which  a  very  fine  needle  and 
thread  may  be  passed  through  it  just  before  using.  As  soon 
as  the  pipette  is  filled,  every  trace  of  blood  must  be  removed 
from  its  outer  surface,  and  the  precaution  taken  to  see  that 
the  column  of  blood  is  exactly  flush  with  the  ends  of  the  tube, 
being  neither  bulged  out  nor  depressed.  The  blood  is  then 
washed  into  one  of  the  compartments  of  the  mixing  chamber, 
by  forcing  a  stream  of  distilled  water  through  the  pipette  by 
means  of  the  glass  dropper,  this  rinsing  being  repeated  until  it 
is  certain  that  every  trace  of  blood  has  been  removed.  The 
preceding  steps  must  be  carried  out  quickly,  in  order  to  avoid 
errors  arising  from  coagulation  of  the  blood.  The  blood  and 
water  in  the  compartment  are  now  thoroughly  mixed,  by  stir- 
ring with  the  handle  of  the  pipette,  until  the  color  of  the  so- 
lution is  uniformly  diffused,  after  which  water  is  added,  drop 
by  drop,  to  each  compartment  until  they  are  both  filled  ex- 
actly to  their  brims.  In  doing  this,  no  water  must  be  spilled 
on  the  thin  edge  of  the  vertical  partition,  for  should  this 
occur  it  may  cause  an  overflow  of  the  liquid  from  one  com- 
partment to  the  other,  and  thus  alter  the  strength  of  the 
blood  solution.  If  the  latter  should  appear  turbid,  or  muddy, 
as  it  sometimes  does  with  leukemic  blood,  a  few  drops  of  a 
weak  aqueous  solution  of  potassium  hydrate  may  be  added  to 
the  diluent  as  a  preventive  of  this  change.  The  addition  of  a 
little  ether  will  clear  the  solution,  if  the  turbidity  is  due  to  the 
presence  of  fat. 

Having  carried  out  the  preceding  steps,  the  mixing  chamber  is 
adjusted  over  the  circular  opening  in  the  stage  of  the  instrument, 
so  that  the  compartment  containing  the  blood  solution  is  upper- 
most, overlying  the  semicircle  illuminated  by  the  clear,  white 
light;  while  the  compartment  filled  with  water  fits  over  the  semi- 
circle which  receives  the  tint  of  the  underlying  glass  wedge. 
The  remainder  of  the  test,  the  comparison  of  the  color  of  the 
two  compartments,  must  be  completed  by  artificial  light  prefer- 
ably by  candle-light.  Moderately  bright  illumination  is  better 
than  a  strong  glare,  for  the  latter  interferes  seriously  with  the 
accurate  determination  of  delicate  color  differences.  By  means 
of  the  milled  wheel  the  tinted  glass  wedge  is  moved  backward 
and  forward  until  its  color  precisely  corresponds  to  that  of  the 
diluted  blood.     When  this  occurs,  the  percentage  of  hemoglobin 


28  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

is  read  off  from  the  scale  visible  through  the  oval   slot  in  the 
stage  of  the  instrument. 

While  making  the  color  comparison  the  obsen'er  should  stand 
facing  one  end  of  the  glass  wedge  {iiot  the  milled  wheel),  so  that 
the  partition  between  the  two  compartments  of  the  mixing  cham- 
ber is  in  a  line  with  the  \'ertical  axis  of  his  eyes,  the  distance  from 
the  latter  to  the  top  of  the  stage  of  the  instrument  being  about 
ten  or  twelve  inches.  Gross  errors  may  be  avoided  if  the  observa- 
tion is  made  with  one  eye,  and  if  the  same  eye  is  habitually  used, 
since  the  two  eyes  may  differ  radically  in  their  sensitiv^eness  to 
color  impressions.  It  is  important  to  decide  the  color  differences 
as  quickly  as  possible,  for  prolonged  examination  rapidly  dulls 
one's  color  perception,  and  creates  uncertainty  as  to  the  proper 
reading.  It  is  a  good  plan  first  to  bring  into  the  field  of  vision 
the  darkest  portions  of  the  wedge  between  the  figures  lOO  and 
1 20  of  the  scale,  and  then,  by  short,  sudden  turns  of  the  milled 
wheel,  to  produce  abrupt  color  contrasts  of  from  5  to  10  de- 
grees at  each  turn,  until  the  two  tints  approximately  correspond.^ 
When  this  point  is  reached  the  eye  should  be  rested  for  a  few 
moments,  and  then,  by  a  succession  of  shorter  turns,  the  wedge 
is  again  swept  to  and  fro  until  the  colors  appear  identical.  In 
the  average  instance  an  error  of  about  5  degrees  must  be  antici- 
pated, in  spite  of  every  precaution  to  insure  accuracy. 

In  cases  in  which  low  hemoglobin  percentages  (30  per  cent., 
or  less)  are  suspected,  it  is  essential  to  use  two  or  three  pipette- 
fuls  of  blood  in  making  the  dilution,  dividing  the  percentage  indi- 
cated by  the  instrument  by  two  or  three,  as  the  case  may  be. 
This  precaution  effectually  removes  the  objection  which  has  been 
urged  against  this  instrument  on  account  of  its  inaccuracies  in 
the  determination  of  low  hemoglobin  percentages.  Another 
criticism  of  the  von  Fleischl  instrument  has  been  made  on  the 
ground  that,  since  the  length  of  the  tinted  wedge  visible  through 
the  compartment  of  the  mixing  chamber  includes  a  color  range 
of  20  per  cent.,  it  is  impossible  for  one  to  select  a  single  point  in 
the  center  of  this  color  for  comparison  with  the  even,  diffuse  tint 
of  the  blood  solution.  This  objection  may  be  overcome  to  a 
great  extent  by  using  a  metal  diaphragm,  provided  with  a  slit 
one-eighth  of  an  inch  in  width,  which  is  placed  over  the  glass 
disc  at  the  bottom  of  the  compartments,  to  limit  the  field  of 
vision.  Adjusted  so  that  the  slit  crosses  at  right  angles  the  par- 
tition separating  the  two  colors,  the  use  of  this  device  cuts  down 

1  It  is  important  to  bear  in  mind  the  fact  that  the  judgment  of  color  differences  is 
much  easier  if  marked  contrasts  in  color  value  are  made,  than  if  a  gradual  blending  of 
the  two  tints  is  attempted,  by  slowly  moving  the  wedge  past  the  visual  field. 


ESTIMATION    OF    THE    PERCENTAGE   OF    HEMOGLOBIN. 


29 


the  field  of  observation  to  a  portion  of  the  glass  wedge  corre- 
sponding to  about  2.5  degrees  on  the  scale. 

The  hemoglobin  percentages  indicated  by  this  instrument  ap- 
pear to  be  low  for  the  blood  of  the  average  healthy  American, 


Fig.  6. 


Method  of  using  the  von  Fleischl  hemometer. 
Note  that  the  septum  between  the  two  halves  of  the  blood  compartment  is  at  right  angles  to  the 
horizontal  axis  of  the  observer's  eyes.      A  cylinder  of  paper  may  be  fitted  over  the  blood  compart- 
meni,  to  serve  as  a  camera-tube. 

since  it  is  more  common  to  obtain  readings  of  from  90  to  95  than 
of  the  arbitrary  standard  100,  in  persons  in  whom  there  is  no 
good  reason  to  suspect  subnormal  hemoglobin  values.  In  in- 
struments of  recent  manufacture,  however,  this  fault  is  largely 
corrected. 


30 


EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 


In  order  to  exclude  the  light  of  the  candle  from  the  field  of 
vision,  while  making  the  color  comparison,  it  is  customar>^  to 
use  a  tube  of  cardboard  or  stiff  paper,  which  is  slipped  over  the 
mixing  chamber,  and  rests  upon  the  platform  of  the  instrument. 
This  sort  of  a  device  answers  very  well  when  the  examination  is 
made  in  a  darkened  room,  as,  for  example,  at  a  patient's  residence. 
In  hospital  work,  however,  the  inconvenience,  sometimes  con- 
siderable, of  being  compelled  to  carr>^  the  diluted  blood  some 
distance  from  the  bedside  to  a  dark-room  may  be  avoided  by  the 
use  of  a  light-proof  box,  which  maybe  conveniently  carried  from 
ward  to  ward,  so  that  the  test  may  be  completed  at  the  bedside. 
(F^g-  7-)     A  box  of  this  kind  should  measure  sixteen    inches 


Fig 


Light-proof  box  for  the  von  Fleischl  hemometer. 
The  door  of  the  box  is  closed  and  the  color  comparison  made  through  the  camera-tube. 

Note. — Reichert,  at  the  suggestion  of  Miescher,  has  recently  introduced  a  modifi- 
cation of  the  original  von  Fleischl  hemometer,  designed  to  increase  the  accuracy  of 
the  test,  by  making  it  possible,  by  definite  dilution  of  the  blood,  to  select  that  part 
of  the  tinted  wedge  which  is  best  adapted  for  the  examination  of  any  particular  sam- 
ple. This  innovation  was  prompted  by  the  discovery  that  the  intermediate  portions 
of  the  wedge  are  better  adapted  for  obtaining  accurate  readings  than  the  terminal 
parts.  The  principal  modification  of  the  new  hemometer  consists  in  the  substitution 
for  the  original  capillary  blood  pipette  of  a  special  mixing  pipette,  similar. to  a 
melangeur,  graduated  so  that  the  blood  may  be  diluted  I  :  200,  i  :  300,  and  I  :  400 
times.  A  table  supplied  with  the  instrument  translates  the  combined  results  of  the 
dilutions  and  the  figures  indicated  by  the  scale  on  the  wedge  into  absolute  hemoglobin 
percentages.  The  instrument  is  also  supplied  with  mixing  chambers  of  different 
depths,  and  with  a  diaphragm  designed  to  limit  the  field  of  vision.  The  writer  has 
had  no  practical  experience  of  the  Miescher-Fleischl  hemometer,  but  an  examination 
of  the  instrument  justifies  the  belief  that  its  elaborateness  renders  it  undesirable  for  gen- 
eral clinical  work.     Its  cost  ($50.00)  is  also  a  bar  to  many. 


ESTIMATION    OF    THE    PERCENTAGE    OF    HEMOGLOBIN.  3 1 

in  height  by  twelve  inches  in  length  and  in  width,  being  fitted 
with  a  hinged  door  which  may  be  fastened  shut  by  a  simple  catch, 
and  provided  with  a  circular  opening  through  which  the  milled 
wheel  of  the  hemometer  projects  when  the  door  is  closed.  A 
metal  camera-tube,  flanged  at  the  upper  extremity  for  the  obser- 
ver's eye,  pierces  the  top  of  the  box  and  communicates  inside 
with  the  mixing  chamber  of  the  hemometer.  The  tube  fits 
loosely  in  a  circular  opening  in  the  top  of  the  box,  so  that 
it  may  be  readily  raised  and  lowered ;  its  diameter  is  a  trifle 
greater  than  that  of  the  mixing  chamber  around  which  it  should 
fit  snugly  when  lowered  into  position  ;  and  its  length  is  governed 
by  a  fixed  collar  outside  the  box,  which  prevents  it  from  slipping 
and  jarring  the  instrument.  Wooden  guides,  such  as  are  used 
for  securing  a  microscope  in  its  box,  are  provided  to  receive  the 
horseshoe  base  of  the  hemometer,  holding  it  firmly  in  such  a 
position  that  when  the  camera-tube  is  lowered  into  position,  the 
milled  wheel  of  the  instrument  projects  through  the  opening  in 
the  closed  door.  The  interior  of  the  tube  and  of  the  box  is 
painted  a  dull  black.  A  candle  is  placed  in  position  on  the  floor 
of  the  box,  in  a  line  with  the  ''  mirror  "  of  the  instrument.  In 
using  this  device,  first  the  candle  within  the  box  is  lighted,  and 
the  hemometer  base  is  slipped  into  place  between  the  wooden 
guides.  The  blood  dilution  having  been  made  in  the  usual  man- 
ner, the  mixing  chamber  is  then  set  upon  the  platform  of  the  in- 
strument, and  the  camera-tube  which  has  been  raised  to  allow 
this  to  be  done,  is  lowered  until  it  telescopes  around  the  mixing 
chamber,  and  rests  firmly  upon  its  collar.  The  door  of  the 
box  is  now  closed,  and  the  two  compartments  are  brought 
into  their  proper  positions  over  the  glass  wedge  by  turning  the 
camera-tube  from  the  outside  of  the  box,  the  observer  mean- 
while noting  the  result  by  looking  through  the  flanged  ex- 
tremity of  the  tube.  This  accomplished,  the  projecting  wheel  of 
the  instrument  is  turned  to  and  fro  until  the  colors  of  the  two 
compartments  are  the  same,  when  the  door  is  opened,  and  the 
percentage  read  off  from  the  scale  of  the  hemometer.  Care 
must  be  observed  to  see  that  the  exterior  of  the  mixing  chamber 
is  perfectly  dry,  for  if  any  moisture  collects  between  its  outer  sur- 
face and  the  inner  surface  of  the  camera-tube,  the  contents 
of  the  compartments  may  be  disturbed  and  serious  errors  re- 
sult. As  the  opening  in  the  door  of  the  box  is  covered  by  the 
hand  with  which  the  milled  wheel  is  turned,  sufficient  light  to 
interfere  with  the  test  cannot  leak  in  at  this  situation. 

With   a  Hght-proof  box  of  this  sort  it  is  possible   accurately 
to  carry  on   hemoglobin   estimations  in  the  brightest   daylight, 


32         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

which  may  be  entirely  excluded  from  the  instrument,  while  the 
observer's  field  of  vision  is  limited  to  the  two  semicircles  illumi- 
nated by  the  candle  burning  within  the  box. 

With  this  instrument  the  principles  of  Lovi- 
Oliver's  bond's  tintometer  are  applied  to  the  quantitative 
Hemoglobin-  estimation  of  hemoglobin,  the  color  of  a  blood 
OMETER.  solution  of  a  definite  strength  being  compared, 
by  light  reflected  from  a  dead  white  surface,  with 
a  series  of  tinted  glass  standards  which  constitute  a  progressive 
color  scale.  Thus,  a  series  of  fixed,  definite  tints  is  provided, 
each  of  which  accurately  corresponds  to  the  specific  color-cur\^e 
of  progressive  dilutions  of  normal  blood,  this  having  been  de- 
termined individually,  by  means  of  the  tintometer.  Two  sets 
of  color  standards  have  been  devised  :  one  for  daylight  readings, 
and  one  for  observations  by  candle  light,  the  latter  being  prefer- 
able on  account  of  the  greater  delicacy  of  its  readings.  Oliver's 
complete  apparatus  consists  of:  (i)  A  capillary  blood  vieastire, 
made  of  hea\y  glass  tubing,  and  having  a  capacity  of  5  cubic 
millimeters.  The  end  to  be  presented  to  the  blood  drop,  in  filling 
the  measure,  is  tapered  to  a  blunt  point,  and  highly  polished. 
(2)  A  7nixi)ig  pipette,  provided  with  a  short  rubber  tube  which 
fits  over  the  tapered  end  of  the  blood  measure,  while  rinsing  out 
the  blood  from  the  latter  into  the  (3)  standard  blood  cell,  which, 
when  filled  exactly  to  the  brim  with  distilled  water  in  which  one 
measureful  of  blood  has  been  dissolved,  yields  a  blood  solution 
of  approximately  one  per  cent.  When  filled,  the  cell  is  covered 
with  a  glass  slip  provided  for  this  purpose.  (4)  A  standard  color 
scale,  consisting  of  1 2  tinted  glass  discs,  mounted  in  two  series, 
and  corresponding  to  hemoglobin  percentages  ranging  from  10 
to  120.  (5)  A  set  of  riders,  or  squares  of  tinted  glass,  used  for 
determining  the  intermediate  degrees  of  color  between  the  deci- 
mals indicated  by  the  fixed  tints  of  the  scale.  For  ordinary  clin- 
ical work  two  riders  are  sufficient,  which  when  laid  over  the  discs 
of  the  standard  scale  read  2.5  and  5  degrees  respectively  on  its 
upper  half,  but  double  this  amount  on  the  lower  half.  For  physi- 
ological observ^ations  requiring  readings  in  units  a  set  of  nine  riders 
is  supplied.  (6)  A  collapsible  ca7nera-tiibe,  through  which  the 
color  comparisons  are  made. 

Method  of  Use.  In  making  hemoglobin  estimations  with 
Oliver's  apparatus,  first  the  capillar)^  measure  is  filled  with  blood 
by  the  method  directed  for  filling  the  pipette  of  the  von  Fleischl 
instrument.  The  rubber  nozzle  of  the  mixing  pipette,  previously 
filled  with  distilled  water,  is  then  adjusted  over  the  polished  end  of 
the  blood  measure,  and  the  blood  washed  into  the  standard  cell  by 


ESTIMATION    OF    THE    PERCENTAGE    OF    HEMOGLOBIN. 


33 


forcing  through  the  water,  drop  by  drop.  As  soon  as  all  of 
the  blood  contained  in  the  bore  of  the  measure  has  been  thus 
washed  out  into  the  cell,  the  rubber  nozzle  of  the  pipette  is  re- 
moved, and  the  handle  of  the  measure  used  as  a  stirrer  to  mix 
the  blood  solution,  more  water  being  added  in  single  drops,  from 
time  to  time,  until  the  cell  is  accurately  filled.  The  blue  cover- 
glass  is  then  adjusted,  with  the  result  that,  if  the  cell  has  not  been 
overfilled,  a  small  air  bubble  forms  on  the  surface  of  the  Hquid. 
The  blood  cell,  filled  in  this  manner  with  a  blood  solution  of 
definite  strength,  is  now  placed  by  the  side  of  the  standard 
scale  opposite  the  tinted  disc  to  which  it  corresponds  most  closely, 
the  eye  readily  recognizing  its  approximate  position  on  the  scale. 
More  accurate  matching  of  the  two  colors  is  made  with  the  aid 
of  the  camera-tube,  the  cell  being  moved  from  disc  to  disc  in  an 
endeavor  to  match  exactly  the  color  of  the  blood  solution  by  one 

Fig.  8. 


Method  of  using  Oliver's  hemoglobinometer. 


of  the  standard  tints  of  the  scale.  If  this  is  successful,  the  hemo- 
globin percentage  indicated  by  the  disc  is  read  off,  and  the  obser- 
vation is  completed.  But  if  it  happens  that  the  tint  of  the  blood 
solution  is  obviously  deeper  than  a  certain  disc,  but  paler  than  the 
3 


34         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

one  immediately  above,  the  cell  is  kept  alongside  the  lower  of  the 
two,  over  which  a  rider  is  adjusted,  in  order  to  deepen  its  color, 
while  the  square  of  white  glass  is  placed  over  the  cell,  so  as  to 
compensate  for  the  thickness  of  the  rider.  If  now  the  colors 
correspond,  the  final  reading  is  ascertained  by  taking  the  percent- 
age of  the  disc  plus  the  value  of  the  superimposed  rider.  If  the 
color  of  the  blood  solution  is  darker  than  that  of  any  one  of  the 
standard  discs,  but  paler  than  the  disc  plus  a  rider,  the  mean 
average  of  the  two  is  taken  as  the  final  reading  ;  similarly,  if  the 
color  of  the  blood  solution  is  darker  than  a  certain  disc  plus  a 
rider,  but  paler  than  the  disc  immediately  above,  the  values  of 
the  two  must  be  averaged.  An  error  of  two  per  cent,  is  un- 
av^oidable,  even  in  the  hands  of  a  skilful  observ^er. 

During  the  observation  the  candle  should  be  placed  three  or 
four  inches  from  the  end  of  the  color  scale,  being  adjusted  so  that 
the  flame  is  in  a  line  with  the  opposed  sides  of  the  cell  and  of  the 
scale,  thus  illuminating  both  with  equal  intensity.  The  positions 
of  the  candle  and  of  the  apparatus  are  shown  in  the  accompanying 
illustration.  (Fig.  8.)  Small  sized  candles,  such  as  are  used 
for  decorating  Christmas  trees,  furnish  a  flame  of  the  proper  de- 
gree of  brilliancy,  the  candle  of  ordinar}^  size  giving  too  intense  a 
light.  Total  exclusion  of  daylight  is  not  necessary-,  so  that  the 
observation  may  be  made  in  the  corner  of  a  partly  darkened 
room,  as,  for  example,  behind  a  closet  door  or  some  other  similar 
shield  against  direct  rays  of  light. 

Oliver's  hemoglobinometer  is  a  trial  to  the  patience  of  one 
who  has  habitually  used  the  von  Fleischl  instrument,  and  it  takes 
some  time  to  become  accustomed  to  it  after  having  worked  with 
the  comparativ^ely  simple  color  comparisons  of  the  hemometer. 
But  the  results  obtained  with  the  newer  instrument  are  so  much 
more  accurate  than  are  possible  with  the  older,  that  no  one  should 
hesitate  in  choosing  Oliver's  apparatus  as  the  better  of  the  two. 
This  instrument,   which   for   many   years  has 
GowERs'        been   popular  in   England  and  is  used  to  some 
Hemoglobin-  extent  in  this  countr}',  consists  essentially  of  tivo 
OMETER.        small  flattened  tubes  of  equal  diameter,  which 
when  in   use   are   fixed   upright  and  parallel  to 
each  other  in  a  small  wooden  support  furnished  for  this  purpose. 
One  tube  contains  glycerine  jelly  colored  with  picrocarmine  to  cor- 
respond to  the  tint  of  a  i   in  lOO  solution  of  normal  blood  (or, 
20  cubic  millimeters  of  blood  in   2  cubic  centimeters  of  water), 
this  being  taken  as  the  standard  with  which  the  blood  solution, 
contained  in  the  second  tube,  is  compared.     The  second  tube  is 
provided  with  a  scale  graduated  in  units  from  5  to   1 20,  each  de- 


ESTIMATION    OF    THE    PERCENTAGE    OF    HEMOGLOBIN. 


35 


Fig,  9. 


GOWERS'    HEMOGLOBI- 
NOMETER. 


gree  of  which  equals  the  volume  of  blood  required  for  the  test. 
Twenty  cubic  millimeters  of  normal  blood,  dissolved  in  sufficient 
distilled  water  to  fill  this  tube  to  the  100  mark  on  the  scale,  give 
a  solution  which  corresponds  to  the  tint  of  the 
standard  tube.  The  special  capillary  pipette  used 
for  measuring  the  blood  is  graduated  at  10  and  at 
20  cubic  millimeters,  and  fitted  with  a  bit  of  rub- 
ber tubing  and  mouthpiece  for  filling  it  by  suc- 
tion. 

Method  of  Use.  The  technique  of  hemoglobin 
estimations  with  Gowers'  apparatus  is  extremely 
simple.  Having  made  the  puncture  in  the  usual 
manner,  the  blood  is  sucked  up  the  caliber  of 
the  capillary  pipette  until  the  mark  20  is  reached, 
and  then  immediately  blown  out  into  the  grad- 
uated tube,  into  which  a  few  drops  of  distilled 
water  previously  have  been  placed,  in  order  to 
insure  instantaneous  solution  of  the  measured 
amount  of  blood.  All  traces  of  blood  which 
may  have  adhered  to  the  bore  of  the  capil- 
lary pipette  are  removed  by  filling  it  several  times  with  water, 
the  rinsings  being  added  to  the  mixture  of  blood  and  water  in  the 
tube.  During  the  preceding  steps  the  usual  precautions  must  be 
observed,  to  wipe  all  surplus  blood  from  the  outside  of  the  pipette 
before  expelling  its  contents,  and  to  measure  the  blood  rapidly  so 
as  to  guard  against  errors  arising  from  rapid  clotting.  Distilled 
water  is  now  added,  drop  by  drop,  to  the  mixture  in  the  tube 
until  the  color  of  the  blood  solution  exactly  corresponds  to  that 
of  the  picrocarmine  standard,  the  contents  of  the  tube  being  mixed 
between  each  addition,  by  rapidly  reversing  it  two  or  three  times, 
with  its  open  end  closed  by  the  thumb.  The  drop  or  two  of 
liquid  adhering  to  the  thumb  should  be  wiped  off  against  the  wall 
of  the  tube  so  that  it  may  drain  back  into  the  liquid.  When  the 
tints  of  both  tubes  are  precisely  similar,  the  division  of  the  scale 
to  which  the  diluted  blood  reaches  is  read  off,  to  express  the  per- 
centage of  hemoglobin  in  the  specimen  under  consideration. 

In  comparing  the  colors,  which  is  done  by  daylight,  the  tubes 
should  be  held  against  a  sheet  of  white  paper,  or,  as  suggested 
by  Gowers,  between  the  eye  and  a  window,  and  viewed  at  such 
an  angle  that  their  adjoining  edges  appear  to  overlap,  thus  cutting 
off  the  vertical  streak  of  white  light  visible  between  them,  should 
this  precaution  be  neglected.  Owing  to  the  diagonal  position  in 
which  the  two  tubes  are  adjusted  in  their  support,  the  proper 
angle  to  produce  this  effect  may  be  readily  determined. 


36 


EXAMINATION    OF    THE    BLOOD    BY    CLINICAL  METHODS. 


The  chief  drawback  to  the  use  of  this  instrument  is  the  Hability 
to  over-dilution  of  the  blood  after  it  has  been  mixed  in  the  grad- 
uated tube,  the  occurrence  of  this  accident  necessitating,  of  course, 
a  repetition  of  the  entire  operation.  To  the  novace  it  is  usually 
hard  to  decide  just  when  sufficient  water  has  been  added  to  the 
blood  to  bring  its  color  donni  to  that  of  the  standard  tint,  since 
one  must  depend  solely  upon  a  gradual  weakening  of  the  tint  of 
the  blood  solution,  and  this  is  much  more  difficult  than  to  com- 
pare a  definite  blood  color  with  the  sHding  scale  of  the  hemom- 
eter,  or  with  the  series  of  discs  of  the  Oliver  apparatus.  The 
instrument  may  be  regarded  as  accurate  within  2  or  3  per  cent, 
for  hemoglobin  percentages   above   10,  below  which  figure  it  is 

.  impossible  to  distinguish  a 
difference  between  the  tints 
of  the  two  tubes.  This 
source  of  error,  however,  is 
too  remote  a  possibility  to 
detract  from  the  instru- 
ment's practical  value. 

Dr.  Ar- 
D are's  thur  Dare, 
Hemoglobin-  of  the  Jef- 
ometer.  fersonHos- 
pital  Med- 
ical Clinic,  has  recently  de- 
vised a  new  form  of  hemo- 
globinometer,  by  the  use 
of  which  a  thin  film  of  iin- 
diluted  blood  is  brought 
into  direct  comparison  with  a 
standard  semicircular  wedge 
of  tinted  glass  ranging  in 
color  from  a  claret  red  at 
the  thickest  part,  to  a  pale 
pink  at  the  thinnest.  The 
instrument  consists  of  the 
following  parts  :  (i)  K cap- 
illary blood  cJiamber,  con- 
structed of  two  rectangular  plates  of  polished  glass,  the  opposed 
surfaces  of  which  are  so  ground  that,  when  clamped  together  in 
a  metal  bracket,  a  shallow  compartment  holding  a  thin  film  of 
blood  is  formed.  One  plate  is  made  of  transparent,  the  other  of 
opaque  glass,  the  latter  being  next  to  the  source  of  light,  in  order 
to  soften  its  glare,  when  the  instrument  is  in   use.     The  metal 


Dare's  hemoglobinometer. 

R,  milled  wheel  acting  by  a  friction  bearing  on  the 
rim  of  the  coloT  disc;  S,  case  enclosing  color  disc,  and 
provided  with  a  stage  to  which  the  blood  chamber  is  fit- 
ted ;  T,  movable  wing  which  is  swung  outward  during 
the  observation,  to  serve  as  a  screen  for  the  observer's 
eyes,  and  which  acts  as  a  cover  to  enclose  the  color  disc, 
when  the  instrument  is  not  in  use  ;  U,  telescoping  camera- 
tube,  in  position  for  examination  ;  V,  aperture  admitting 
light  for  illumination  of  the  color  disc  ;  X,  capillary 
blood  chamber  adjusted  to  stage  of  instrument,  the  slip 
of  opaque  glass,  W,  being  nearest  to  the  source  of  light  ; 
Y,  detachable  candle-holder  ;  Z,  rectangular  slot 
through  which  the  hemoglobin  scale  indicated  on  the 
rim  of  the  color  disc  is  read. 


ESTIMATION    OF    THE    PERCENTAGE    OF    HEMOGLOBIN. 


17 


Fig.   II. 


bracket  of  the  blood  chamber  is  adjusted  to  the  stage  of  the  in- 
strument in  such  a  manner  that  the  blood-film  fits  over  an  aper- 
ture communicating  with  a  camera-tube  screwed  to  the  op- 
posite side  of  the  rubber  case.  (2)  A  graduated  color  standard 
made  of  a  semicircle  of  glass  tinted  with  Cassius'  ''golden- 
purple,"  and  thinning  out  like  a  wedge  with  various  depths  of 
color  corresponding  to  the  tints  of  fresh  blood  containing  dif- 
ferent percentages  of  hemoglobin.  It  is  mounted  upon  a  disc  ad- 
justed in  the  frame  of  the  instrument  so  that  it  may  be  revolved 
to  bring  various  portions  of  its  surface  over  an  aperture  directly 
alongside  of  the  one  through  which  the  blood  film  is  vis- 
ible. A  scale,  read  from  the  outside  of  the  instrument,  in- 
dicates in  units  the  hemoglobin  percentages  from  10  to  120. 
(3)  A  Jiard  rubber  case  encloses  the  color  standard,  when 
the  instrument  is  in  use,  the  disc  upon  which  the  standard  is 
mounted  being  revolved  by  turning  a  small  milled  wheel  acting 
upon  the  rim  of  the  disc  by  a  friction 
bearing.  To  one  side  of  the  case  a 
telescopic  camera-tube,  fitted  with  an 
eye-piece,  is  attached,  while  on  the 
opposite  side  a  stage  furnishes  support 
for  the  blood  chamber,  back  of  which 
a  candle,  held  between  a  pair  of  spring 
clips,  is  adjusted.  Two  apertures  of 
equal  diameter,  placed  side  by  side 
on  the  same  level,  transmit  the  light 
of  the  candle  through  the  blood-film 
and  the  color  standard  to  the  field  of 
vision  enclosed  by  the  camera-tube. 
By  reference  to  the  accompanying 
diagram  (Fig.  11),  it  will  be  seen  that 
the  light  of  the  candle,  J,  equally  illu- 
minates the  blood  film  enclosed  be- 
tween the  two  rectangular  glass  plates, 
O   and  P,  and  the  edge  of  the  color 

standard,  L,  mounted  upon  the  glass  disc,  K.  The  differences 
in  the  two  colors  are  visible  through  the  two  apertures,  M  and 
M',  communicating  with  the  camera-tube,  N.  By  revolving 
the  disc  the  tint  of  the  color  standard  may  be  altered  until  it 
matches  that  of  the  blood-film. 

Method  of  Use.  The  instrument  is  prepared  for  use  by  first 
swinging  outward  the  movable  screen  which  serves  as  a  cover  for 
the  case.  The  two  apertures  overlying  the  blood-film  and  the 
color  scale  are  thus  brought  into  view,  the  direct  light  from  the 


Horizontal  section  of  Dare's 
hemoglobinometer. 


38 


EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 


Manner  of  filling  blood  chamber. 


candle  being  shaded  from  the  observ^er's  eyes  by  the  intervening 
screen.  The  camera-tube  and  the  candle-holder  are  then  fitted  to 
their  attachments  on  opposite  sides  of  the  instrument,  and  a  candle 
adjusted  so  that  the  surface  of  its  "  wick  end  "  is  just  on  a  level 
with  the  top  of  the  spring  clips. 

The  blood  chamber  is  filled  by  touching  its  edge  to  the  side  of 
a  rather  large  drop  of  blood,  as  the  latter  flows  from  the  punc- 
ture, so  that  the  blood 
^^^'  ^^'  at  once  flows  into  and 

fills,  by  capillar}^  force, 
the  shallow  compart- 
ment between  the  pair 
of  glass  plates.  As 
soon  as  this  occurs, 
any  excess  of  fluid 
which  may  have  ad- 
hered to  the  outer  sur- 
face of  the  blood  cham- 
ber is  carefully  wiped 
away,  and  the  latter 
is  slipped  into  the  tongue  which  holds  it  in  position  on  the  stage 
of  the  instrument. 

The  candle  having  been  lighted,  the  observ-er  holds  the  instru- 
ment as  a  field  glass,  and  compares  with  one  eye  the  colors  of 
the  blood-film  and  the  standard  disc  which  are  seen  side  by  side 
in  the  field  of  vision  limited  by  the  camera-tube.  The  disc  is 
made  to  revolve  by  making  short,  quick  turns  with  the  milled 
wheel,  until  the  two  colors  are  identical,  and  the  hemoglobin 
percentage  indicated  by  the  scale  is  then  noted. 

The  color  comparisons  need  not  be  made  in  a  darkened  room, 
although  the  obser\^er  should  avoid  facing  the  direct  sunlight, 
and,  in  order  to  exclude  reflected  hght,  should  hold  the  instru- 
ment against  a  dark  surface,  such  as  a  black  coat  sleeve.  When 
the  observation  is  completed,  the  two  glass  plates  of  the  blood- 
chamber  are  removed  from  the  bracket  by  loosening  the  screw 
which  holds  them  in  position.  They  are  then  cleaned  with  water 
and  with  acid  alcohol,  dried,  polished,  and  replaced  in  the  bracket. 
The  various  parts  of  the  instrument,  when  detached,  fit  into  a  small 
leather  carr)^ing-case. 

The  chief  advantage  of  Dare's  instrument  lies  in  the  fact  that 
dilution  of  the  blood  is  not  required,  and  therefore  errors  due  to 
incorrect  measuring  and  dilution  of  the  blood,  which  must  be  care- 
fully guarded  against  in  the  older  hemoglobinometers,  are  entirely 
eliminated.     A  film  of  whole  blood  also  gives  a  relatively  deep 


ESTIMATION    OF    THE    PERCENTAGE    OF    HEMOGLOBIN.  39 

and  definite  color,  which  may  be  judged  with  greater  ease  and 
accuracy  than  the  paler  and  more  indefinite  tint  of  a  blood  solu- 
tion. It  is  also  obvious  that  errors  due  to  the  turbidity  of  an 
aqueous  solution  of  leukemic  blood,  are  avoidable  by  the  use  of 
an  undiluted  film.  Coagulation  of  the  film  does  not  occur  with  suf- 
ficient rapidity  to  constitute  a  source  of  error,  since  the  test  may 
be  completed  within  a  few  seconds  after  the  blood  has  been  drawn. 

One  year's  more  or  less  constant  use  of  this  instrument  in  the 
Jefferson  Medical  Clinic  has  shown  that  its  readings  closely  cor- 
respond to  those  of  Oliver's  hemoglobinometer,  and  average  some- 
what higher  than  those  of  the  von  Fleischl  instrument.  The  color 
standard  of  Dare's  apparatus,  being  wedge-shaped,  and  therefore 
gradually  blending  the  tints,  is  open  to  the  same  criticisms  which 
have  been  urged  against  the  scale  of  the  hemometer. 

A  simple  method  of  approximately  determin- 
Tallquist's  ing  hemoglobin  percentages  without  the  aid  of 
Method.  a  special  instrument  has  recently  been  devised 
by  Tallquist,^  the  procedure  consisting,  in  brief, 
in  allowing  a  drop  of  blood  to  soak  into  a  bit  of  filter-paper  and 
comparing  with  the  naked  eye  the  color  strength  of  the  stain 
with  a  series  of  printed  standard  tints  of  known  value.  The  lat- 
ter are  arranged  as  a  scale  of  ten  different  colors  corresponding 
to  the  colors  of  stains  produced  by  bloods  having  hemoglobin 
values  ranging  from  loto  lOO  per  cent.,  the  latter  being  regarded 
as  the  normal.  A  lithographed  copy  of  the  color  standard  ac- 
companies Tallquist's  original  article.  The  test  is  made  in  the 
following  manner :  A  drop  of  blood,  large  enough  to  make  a 
stain  about  five  or  six  millimeters  in  diameter,  is  caught  in  the 
center  of  a  piece  of  white  filter-paper,  care  being  taken  in  col- 
lecting it  to  apply  the  paper  to  the  exuding  drop  in  such  a  man- 
ner that  the  blood  soaks  in  very  slowly,  and  thus  produces  a 
stain  which  is  evenly  colored  throughout.  Perfectly  white  filter- 
paper  having  a  smooth  surface,  and  of  a  thickness  corresponding 
to  about  fifty-five  leaves  to  the  centimeter,  should  be  used  for  the 
test.  The  blood  stain  thus  made  is  pressed  lightly  against  a  pad 
of  filter-paper,  and  then  compared,  by  direct  daylight,  with  the 
series  of  standard  tints,  the  figure  opposite  to  the  tint  which  the 
stain  most  accurately  matches  being  read  off,  to  indicate  the  per- 
centage of  hemoglobin  in  the  specimen  under  examination.  The 
comparison  must  be  made  immediately  after  the  stain  loses  its 
humid  gloss,  since  blood  soon  changes  its  color  after  exposure  to 
the  air. 

This  direct  method  of  hemoglobin  testing  is,  of  course,  only 

^St.  Paul  Med.  Jonrn.,  1900,  vol.  ii.,p.  291. 


40         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

approximate,  at  the  best,  and  cannot  be  expected  to  furnish  re- 
sults comparable  in  point  of  accuracy  with  those  to  be  obtained 
by  any  of  the  instruments  just  described.  It  may,  however,  be 
employed  to  excellent  advantage  when  a  hemoglobinometer  is 
not  at  hand,  or  in  certain  cases  in  which  only  a  rough  estimate  of 
the  amount  of  coloring  matter  of  the  blood  is  sought.  Tall- 
quist,  who  has  tested  his  method  under  the  control  of  the  he- 
mometer,  in  his  clinic  at  Helsingfors,  claims  that  the  limit  of  error 
generally  does  not  exceed  ten  per  cent. 

III.     COUNTING    THE    ERYTHROCYTES   AND   THE 

LEUCOCYTES. 

Of  the  various  instruments  used  for  counting 
Methods.  the  blood  corpuscles,  the  hemocytometers  de- 
vised by  Thoma  and  by  Gowers  are  most  gener- 
ally employed  at  the  present  time,  the  former  being  used  almost 
to  the  exclusion  of  the  latter  everywhere  except  in  England, 
where  Gowers'  apparatus  has  many  firm  adherents.  Durham, 
by  adapting  and  modifying  a  number  of  the  details  of  the  older 
instruments,  has  succeeded  in  devising  an  improved  form  of  hemo- 
cytometer  which  possesses  many  advantages  over  the  original 
models,  being  of  simple  construction,  accurate,  and  comparatively 
inexpensive.  The  method  of  making  the  estimate,  which  is  es- 
sentially the  same  with  all  three  of  these  instruments,  consists, 
briefly,  in  first  diluting  the  fresh  blood  in  definite  proportions  with 
some  indifferent  preser\^ative  fluid,  and  in  then  counting,  under 
the  microscope,  the  number  of  corpuscles  in  a  drop  of  the  di- 
luted blood,  the  latter  being  contained  in  a  small  glass  cell  on 
the  floor  of  which  is  ruled  a  series  of  micrometer  squares  of  cer- 
tain dimensions.  The  cubic  contents  of  the  cell  and  the  degree 
of  the  blood  dilution  being  known,  the  number  of  corpuscles 
counted  in  any  given  number  of  these  squares  may  be  taken  as 
a  basis  for  calculating  the  total  count  of  corpuscles  to  the  cubic 
millimeter  of  blood. 

In  addition  to  the  method  of  actually  counting  the  corpuscles  in 
a  known  volume  of  diluted  blood,  Oliver  has  devised  an  instru- 
ment with  which  the  number  of  erythrocytes  may  be  estimated 
by  means  of  their  optical  effect,  without  the  use  of  the  microscope. 
Diluting  fluids  for  use  with  the  hemocytom- 
DiLUTiNG       eters  of  Thoma,  Gowers,  and  Durham  should 
Fluids.        be  of  such  a  composition  that  when  mixed  with 
the  fresh  blood  they  preserve  unaltered  the  form 
of  the  corpuscles.     This  requirement  being  met,  the  examiner 


COUNTING    THE    ERYTHROCYTES    AND    THE    LEUCOCYTES.         4 1 

may  choose  from  the  numerous  formulae  in  current  use  the  one 
which  best  suits  his  individual  preference.  Among  the  most  sat- 
isfactory solutions  used  for  this  purpose  the  following  may  be 
mentioned  : 

Toisson's  Solution. 

Methyl-violet,  5  B 0.025 

Sodium  chloride  i.o 

Sodium  sulphate  , 8.0 

Neutral  glycerine 30.0 

Distilled  water 160.0 

Sherrington's  Solution. 

Methylene-blue o.i 

Sodium  chloride  1.2 

Neutral  potassium  oxalate 1.2 

Distilled  water 300.  o 


For  general  clinical  work  no  better  formulae  have  ever  been 
suggested  than  the  preceding  two.  Both  solutions  act  as  excel- 
lent preservative  fluids,  and  each  contains  just  sufficient  quantity 
of  a  basic  aniline  dye  to  stain  the  leucocytes  with  great  distinct- 
ness, so  that  they  may  be  readily  differentiated  from  the  erythro- 
cytes, which  remain  uncolored. 

Hayem's  Solution. 

Mercuric  chloride 0.25 

Sodium  chloride 0.5 

Sodium  sulphate 2.5 

Distilled  water 100. o 

Oliver  specifies  this  solution  as  the  diluent  invariably  to  be 
employed  with  his  instrument,  but  it  may  be  used  also  with  the 
other  forms  of  hemocytometers,  although  with  less  satisfaction 
than  the  formulae  first  mentioned. 

Among  the  simpler  diluting  fluids,  all  of  which  are  depend- 
able, are  solutions  in  distilled  water  of  common  salt  (0.7  per  cent.), 
of  potassium  bichromate  (2.5  per  cent.),  and  of  sodium  sulphate 
(5  per  cent.),  to  any  of  which  about  0.5  per  cent,  of  an  alco- 
holic solution  of  methyl-violet  may  be  added,  in  order  to  stain 
the  leucocytes,  and  thus  to  facilitate  the  counting. 

An  aqueous  solution  of  acetic  acid,  varying  in  strength  from 
0.3  to  0.5  per  cent.,  which  destroys  the  erythrocytes  and  at  the 
same  time  renders  more  conspicuous  the  leucocytes,  has  been 
recommended  by  Thoma  as  a  diluent  in  counting  the  latter  cells, 
by  means  of  his  special  pipette. 


42 


EXAMINATION    OF    THE    BLOOD    BV    CLINICAL    METHODS. 


Fig.  i^. 


As  spores  are  liable  to  develop  and  precipitates  to  form  in  all 
the  above-mentioned  solutions,  they  should  always  be  filtered 
before  using,  and  kept  in  tightly  corked  bottles. 

The    Thoma-Zeiss   hemocytometer,  which    is 
The  Thoma-    to-day  regarded  as  the  standard  instrument  for 
Zeiss  Hemo-    blood  counting,  consists  of  two  graduated  capil- 
CYTOMETER.     lar}^  pipcttes,  for  diluting  and  mixing  the  blood, 
and   a  counting   chamber  in  which  a   measured 
volume  of  diluted  blood  is  placed  for  the  purpose  of  counting  the 
corpuscles  under  the  microscope.      One  of  the  pipettes  is  intended 
for  counting  the  erj^throcytes,   and,  for    con- 
venience's sake,   may  be  termed  the  erjthro- 
cytometer ;    while  the  other  pipette,  which  is 
used    for    counting    the    leucocytes,    may    be 
called  the  leucocytometer.      It  is  not,  however, 
necessary  to  purchase    both   pipettes,  as  sup- 
plied with  the  complete  apparatus,  since  both 
er)'throcytes   and  leucocytes  may  be  counted 
accurately  with  the  erj^throcytometer. 

The  crytJiJ'ocytoineter  consists  of  a  heavy 
glass  capillar}'  tube,  the  lumen  of  which  is 
expanded  near  the  upper  end  into  a  bulb  con- 
taining a  small  cubical  glass  bead,  which 
serves  as  a  stirrer.  The  lower  end  of  the  tube 
is  ground  to  a  blunt  point,  and  to  the  upper  end 
is  fitted  a  short  bit  of  rubber  tubing  capped  by 
a  bone  mouthpiece,  for  filling  the  tube  by  suc- 
tion. A  scale  is  enameled  into  the  glass  wall 
of  the  pipette,  the  three  main  divisions  of  which 
are  indicated  by  the  figures,  0.5,  i,  and  loi, 
the  first  two  gradations  being  below,  and  the 
latter  one  above,  the  bulb  ;  the  lower  portion 
of  the  tube  is  further  graduated  in  tenths,  by 
cross  lines,  from  o.i  to  i.  If  blood  is  drawn 
up  in  the  pipette  to  the  mark  i ,  and  the  diluent 
added  until  the  mark  loi  is  reached,  the  blood 
is  thus  diluted  one  hundred  times  ;  or  if  the 
blood  is  drawn  up  only  to  the  mark  0.5,  and 
the  diluent  added  as  before,  a  two  hundred-fold 
dilution  is  obtained. 

The  laicocytonicter  is  a  capillar}'  tube  similar 

to  the  former,  but  having  a  larger  lumen,    so 

that  lowe  r  dilutions  are  obtained  with  it.      If  blood  is  drawn  up  to 

the  mark  i ,  and  the  diluent  added  until  the  mixture  reaches  the 


Bl 


V 


]l 


The  Thoma-Zeiss 
hemocytometer.  a, 
erythrocytometer;  B, 
leucocytometer. 


COUNTING    THE    ERYTHROCYTES    AND    THE    LEUCOCYTES. 


43 


mark  1 1,  the  blood  is  diluted  ten  times  ;  or  if  the  blood  column 
reaches  the  mark  0.5,  with  the  same  addition  of  diluent,  the  dilu- 
tion thus  made  is  twenty-fold.  In  the  latest  model  of  this  pipette 
the  lower  end  tapers  to  a  fine  point,  the  diameter  of  the  lumen 
thus  gradually  decreasing  as  the  extreme  tip  is  approached.  The 
chief  object  of  this  modification  is  to  prevent  accidental  leaking 
out  of  the  column  of  blood  when  the  tube  is  held  vertically,  while 
sucking  up  the  diluting  fluid — an  accident  difficult  to  avoid  with 
the  old-style  pipette,  having  a  large  lumen  from  tip  to  bulb. 

The  counting  cJiamber  (Fig.  14)  consists  of  a  heavy  glass  slide  in 
the  center  of  which  is  cemented  a  square  glass  plate  provided  with 
a  circular  opening  which  fits  around  a  ruled  disc  ;  the  diameter  of 
the  latter  being  slightly  less  than  that  of  the  opening  in  the  sur- 
rounding plate,  a  shallow,  narrow  gutter  is  thus  formed  between 
the  two.  The  surface  of  the  ruled  disc  is  exactly  -^^  millimeter 
below  the  level  of  the  glass  plate  by  which  it  is  enclosed,  so 

Fig.  14. 


Thoma-Zeiss  counting  chamber. 


that  a  chamber  of  this  depth  is  formed  when  both  are  superim- 
posed by  a  cover-glass  having  an  absolutely  plane  surface,  two  of 
which  are  furnished  with  each  instrument.  An  ordinary  cover- 
glass  should  never  be  used,  for  owing  to  the  unevenness  of  its 
surface  a  deviation  from  the  standard  in  the  depth  of  the  underly- 
ing chamber  must  necessarily  result.  When  an  objective  having 
an  extremely  close  ''working  distance"  is  employed,  the  special 
hollow-cell  cover-glass,  made  by  Zeiss,  will  prove  useful. 

The  central  part  of  the  disc's  surface  is  divided,  by  microscopical 
diamond-rulings,  into  400  small  squares,  each  of  which  has  an  area 
of  ^-J-Q-  square  millimeter,  these  small  squares  being  grouped  into 
sets  of  sixteen,  by  a  series  of  vertical  and  horizontal  double  rul- 
ings bisecting  each  fifth  column  of  squares.  (Fig.  15.)  The 
cubic  contents  of  each  small  square,  when  the  cover-glass  is  ad- 
justed, is  -^-^-^-^  cubic  millimeter,  since  they  measure  individually 


44 


EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 


tV  by  2V  ^y  2V  n^illirneter.      In  Zappert's  modified  ruling  of  the 
Thoma-Zeiss  counting  chamber,  extra  Hnes  have  been  added  so  as 

Fig.  15. 


Ruled  area  of  the  Thoma-Zeiss  counting  chamber  (ordinaky  ruling). 

to  increase  the  ruled  area  of  the  disc  to  nine  times  its  original 
size.     As  illustrated  in  the  accompanying  diagram  (Fig.  16),  the 

Fig.  16. 

iiiiii  mil 


{IIIM 


liiiliiiiii 


T 


Zappert's  modified  ruling  of  the  Thoma-Zeiss   counting  chamber. 

surface  of  the  disc  is  thus  divided,  by  heavy  cross-rulings,  into  nine 
large  squares  each  equal  in  area  to  the  central  group  of  400  small 


COUNTING  THE  ERYTHROCYTES  AND  THE  LEUCOCYTES.    45 

squares,  the  whole  ruled  surface  therefore  equalling  an  area  covered 
by  3,600  of  the  latter.  To  simplify  the  counting,  the  peripheral 
squares  are  subdivided  into  four,  each  of  the  latter  being  of  the 
same  area  as  lOO  of  the  small  central  squares.  This  improved  form 
of  counting  chamber  is  an  invaluable  convenience  in  leucocyte 
counting,  and  should  be  chosen  in  preference  to  the  older  model. 
If  any  difficulty  should  be  experienced  in  distinguishing  the 
ruled  lines  under  the  microscope,  they  may  be  made  more  con- 
spicuous by  blackening  them  with  a  little  soft  lead  pencil  dust, 
placed  on  the  surface  of  the  disc  and  thoroughly  rubbed  in  with 
the  pulp  of  the  finger,  the  excess  being  wiped  off  and  the  disc 
polished  with  a  bit  of  lens-paper,  or  a  soft  handkerchief. 

Fig.  17. 


Method  of  filling  the  capillary  tube  of  the  Thoma-Zeiss  hemocytometer  with  blood. 


Counting  the  Erythrocytes.  Having  made  the  puncture,  as 
already  described,  the  point  of  the  erythrocytometer  is  plunged 
into  the  blood  drop,  as  it  flows  from  the  wound,  and,  by  making 
gentle,  uniform  suction,  a  column  of  blood  is  drawn  up  the  capil- 
lary tube  exactly  to  the  mark  0.5.     The  point  of  the  instrument 


46  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

is  then  wiped  perfectly  dry,  and  immediately  dipped  into  the  diluting- 
fluid,  which  is  drawn  up  the  tube  in  the  same  manner  until  the 
mixture  of  blood  and  diluent  reaches  the  mark  10 1,  above  the 
bulb.  While  adding  the  diluent,  the  pipette  should  be  twisted  to 
and  fro  between  the  thumb  and  forefinger,  in  order  that  the  blood 
and  diluent  may  be  mixed,  by  the  whipping  about  of  the  glass 
bead,  as  they  fill  the  bulb  ;  if  this  precaution  is  neglected,  a  por- 
tion of  the  blood  will  rise  in  a  distinct  layer  above  the  diluent,  as 
the  latter  flows  into  the  bulb,  and  may  be  drawn,  unmixed,  into 
the  capillary  constriction  beyond.  A  more  thorough  mixture  of 
the  blood  and  diluent  is  now  made,  the  rubber  tubing  being 
slipped  from  the  instrument,  which  is  then  grasped  so  that  its 
ends  are  closed  by  the  thumb  and  middle  finger,  and  rapidly 
shaken  for  about  half-a-minute.  By  the  above  steps,  a  mixture 
is  made  in  which  the  proportion  of  blood  to  diluent  is  i  :  200,  a 
degree  of  dilution  with  which  it  is  most  convenient  to  work,  in 
the  great  majority  of  instances.  For  two  reasons  a  i  :  200,  rather 
than  a  i  :  100,  dilution  is  to  be  preferred  in  routine  work:  (i) 
If,  as  not  infrequently  happens,  the  blood  column  is  accidentally 
drawn  up  the  tube  beyond  the  mark  0.5,  in  an  attempt  exactly 
to  reach  this  gradation,  it  is  a  simple  matter  to  correct  the  error 
by  gently  blowing  or  shaking  the  blood  column  down  to  the 
proper  height ;  whereas,  in  attempting  to  make  a  i  :  100  dilution, 
should  the  mark  i  be  exceeded,  the  blood  column  will  almost 
surely  escape  into  the  bulb  whence  it  cannot  be  blown  back  again 
into  the  capillary  tube,  thus  necessitating  a  repetition  of  the 
whole  operation  with  a  fresh  drop,  after  having  cleaned  and  dried 
the  erythrocytometer.  (2)  It  is  easy  to  count  the  corpuscles 
in  a  I  :  200  dilution,  since  the  surface  of  each  ruled  square  of  the 
counting  chamber  is,  as  a  rule,  occupied  by  not  more  than  half 
a  dozen  cells  ;  on  the  contrary,  in  a  i  :  100  dilution,  except  in 
an  occasional  instance  in  which  there  is  a  striking  paucity  of  cells, 
the  field  may  be  so  overcrowded  with  corpuscles  that  their  enu- 
meration is  difficult,  and  often  inaccurate. 

The  next  step  is  to  place  a  drop  of  the  diluted  blood  in  the 
counting  chamber,  preparatory  to  counting  the  corpuscles  under 
the  microscope.  The  unmixed  diluting  fluid  in  the  lower  portion 
of  the  capillary  tube  is  first  expelled,  by  blowing  out  four  or  five 
drops,  after  which  the  point  of  the  pipette  is  dried  with  a  soft 
cloth,  and  a  small  drop  of  the  blood  mixture  is  allowed  to  fall, 
by  force  of  gravity,  exactly  in  the  center  of  the  surface  of  the 
ruled  disc.  The  cover-glass  is  then  immediately  placed  in  posi- 
tion, and  the  slide  left  undisturbed  for  several  minutes,  so  that 
the  corpuscles  may  settle.     The  drop  placed  on  the  disc  should 


COUNTING   THE    ERYTHROCYTES    AND    THE   LEUCOCYTES.         4/ 

be  of  sufficient  size  to  occupy  only  its  central  portion,  the  object 
being  to  use  just  enough  of  the  blood  mixture  to  cover  the  ruled 
area  and  exactly  to  fill  in  the  vertical  space  between  the  surfaces 
of  the  disc  and  cover-glass  when  the  latter  is  placed  in  position. 
If  the  drop  contains  air-bubbles,  or  if  it  is  so  large  that  it  over- 
flows into  the  gutter  and  perhaps  finds  its  way  between  the  cover- 
glass  and  the  glass  plate  beneath,  errors  will  result,  so  that  in 
event  of  either  of  these  accidents  the  procedure  must  be  repeated 
with  another  drop,  after  having  cleaned  and  dried  the  cover-glass 
and  the  counting  chamber.  Water,  and  not  alcohol  or  xylol,  is 
to  be  used  for  this  purpose,  since  the  repeated  use  of  chemicals 
will  soon  dissolve  the  cement  which  fixes  the  disc  to  the  counting 
chamber.  In  repeating  the  operation  the  original  technique  must  be 
rigidly  followed,  i.  ^.,  the  erythrocytometer  must  be  briskly  shaken 
for  half  a  minute  or  so,  and  the  contents  of  its  capillary  stem  blown 
out,  before  placing  the  new  drop  in  the  counting  chamber. 

In  a  properly  prepared  slide  concentric  rings  of  color — New- 
ton's rings — may  be  seen  at  the  points  of  contact  between  the 
cover-glass  and  the  underlying  glass  plate.  If  these  rings  are  in- 
visible, or  if  they  do  not  appear  when  pressure  is  made  upon  the 
cover-glass,  it  is  a  sign  that  the  contact  between  the  two  glass 
surfaces  is  not  true,  this  being  due  to  the  presence  of  particles  of 
dust  or  of  moisture  beneath  the  cover-glass.  Inasmuch  as  this  may 
seriously  affect  the  correctness  of  the  count,  it  is  a  safe  rule  invari- 
ably to  reject  a  slide  in  which  these  color  rings  are  not  visible. 

As  soon  as  sufficient  time  has  elapsed  for  the  corpuscles  to 
sink  to  the  bottom  of  the  counting  chamber — about  five  minutes 
— the  slide  is  transferred  to  the  stage  of  the  microscope,  which 
should  not  be  incHned,  for  fear  of  disturbing  the  uniform  distribu- 
tion of  the  cells.  The  field  is  first  brought  into  focus  with  a  low- 
power  objective  (a  No.  3  objective  of  Leitz,  for  example),  and  the 
slide  moved  across  the  stage  until  the  extreme  upper  left-hand 
corner  of  the  group  of  small  ruled  squares  is  brought  into  view, 
when  a  higher  power,  to  be  used  in  counting,  is  substituted. 
For  this  purpose  the  writer  is  accustomed  to  use  a  Leitz  No.  6 
objective  and  No.  4  ocular,  which  lenses,  with  a  tube  length  of 
155  mm.,  cut  off  a  field  occupied  by  a  block  of  25  small  squares. 

As  a  basis  for  the  final  calculation,  the  erythrocytes  in  400 
small  squares,  or  the  entire  ruled  surface  of  the  old-style  disc, 
should  be  counted,  preferably  by  going  over  two  groups  of  200 
squares  each  in  two  different  drops,  rather  than  by  taking  the  en- 
tire 400  squares  in  a  single  specimen.  By  following  this  plan  the 
count  of  one  drop  may  be  **  controlled  "  by  the  count  of  the  other, 
and  any  discrepancy  between  the  two  discovered,  for  if  the  dif- 


48 


EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 


ference  in  the  counts  is  striking,  a  third  group  of  200  squares 
must  be  examined  in  an  additional  drop,  and  an  average  taken 
of  the  two  counts  which  most  closely  correspond. 

In  order  to  simplify  the  process  of  counting,  some  routine 
method  of  examining  the  ruled  area,  such  as  the  following,  should 
be  adopted  :  Beginning  at  the  upper  left-hand  corner  of  the  ruled 
disc,  the  corpuscles  in  the  first  100  small  squares  are  counted, 
the  slide  being  moved  from  above  downward,  preferably  by  the 
aid  of  a  mechanical  stage,  as  the  successive  groups  of  squares  are 
covered.  By  employing  the  magnification  to  which  reference  has 
just  been  made,  three  shifts  of  the  slide  are  sufficient  to  bring 
into  the  field  the  requisite  number  of  squares  in  blocks  of  25 
each.  Examining  each  small  square  in  succession,  proceed  from 
left  to  right  along  one  row  of  fiv'e,  then  drop  to  the  next  row  and 

Fig.   18. 


Pl.\n  of  counting  the  ervthrocytes. 

The  small  squares  are  examined  in  the  order  indicated  by  the  arrow,  successive  blocks  of  25  squares 
being  covered  until  the  required  number  of  cells  has  been  counted. 

count  from  right  to  left,  and  continue  in  the  manner  illustrated 
by  the  diagram  (Fig.  i8)  until  all  the  er)-throcytes  in  the  first 
group  of  100  squares  have  been  counted,  the  totals  of  each  block 
of  25  squares  being  noted  as  they  are  completed.  To  avoid  repe- 
tition in  counting  it  is  necessar>'  to  include  in  the  total  all  the  cor- 
puscles which  touch  the  upper  and  left  boundar}'  hnes,  and  to 
disregard  those  which  touch  the  lower  and  right  boundaries.  A 
second  group  of  lOO  squares,  not  immediately  adjacent  to  the 


COUNTING  THE  ERYTHROCYTES  AND  THE  LEUCOCYTES.    49 

first,  is  then  inspected  in  a  similar  manner,  after  which  the  cover- 
glass  and  counting  chamber  are  washed  with  water  and  dried,  and 
the  operation  repeated  with  a  second  drop.  Thus  the  400  squares 
are  covered  by  examining  16  blocks  of  25  squares  each,  8  in  the 
first,  and  8  in  the  second  drop  of  diluted  blood.  In  a  i  :  200  di- 
lution of  normal  blood  this  involves  the  counting  of  approxi- 
mately from  2,400  to  2,800  er}^throcytes,  and  gives  results  which 
are  accurate  within  one-and-one-half  per  cent. 

To  calculate  the  number  of  erythrocytes  to  the  cubic  milli- 
meter of  blood,  the  following  formula  is  employed  : 

Number  of  eryth-  Degree  of  dilu-  Cubic  contents  '  Total  num- 
rocytes  counted      x  tion  (206)  x  of  each  square      beroferyth- 

(^,000)  rocytes  per 

Number  of  squares  cotmted  {4.00)  ^^-  ^^• 

For  example,  supposing  that  in  the  400  squares  of  a  i  :  200 
blood  dilution  a  total  of  2,500  erythrocytes  is  counted,  the  cal- 
culation is  made  thus  : 

,  .  2,500  X  200  X  4,000  , 

{a) =  5,000,000  e^ytlirocytes per  cb.  mm. 

{b)         2,500x2,000       =  ''  "  ''     ''      '' 

Counting  the  Leucocytes.  The  leucocytes  may  be  counted  by 
two  different  methods  :  (a)  with  the  erythrocytometer,  in  the 
same  drop  of  diluted  blood  in  which  the  erythrocytes  are  esti- 
mated ;  or  (^b)  with  the  special  leucocytometer,  as  a  separate  pro- 
cedure. Of  the  two  methods  the  former  is  greatly  to  be  preferred, 
since  it  is  fully  as  accurate,  and  much  more  convenient  and  time- 
saving  than  the  latter.  Furthermore,  there  is  an  undoubted  ad- 
vantage in  counting  both  the  red  and  the  white  corpuscles  in  the 
same  drop  of  the  blood  dilution. 

{a)  If  the  leucocytes  are  counted  with  the  erythrocytometer 
the  same  technique  is  followed  as  in  determining  the  number  of 
erythrocytes,  except  that  a  much  larger  area  of  the  counting 
chamber  must  be  examined,  owing  to  the  comparatively  small 
number  of  leucocytes  contained  in  the  i  :  200  blood  mixture. 
It  is  necessary,  for  the  sake  of  accuracy,  to  count  the  leucocytes 
in  the  entire  space  enclosed  by  Zappert's  ruling,  and  to  repeat  the 
coufit  in  a  second  drop,  making  an  area  equal  to  eighteen  times 
the  ruled  space  of  the  old-style  counting  chamber  to  be  examined. 
If  the  totals  of  both  counts  are  approximately  the  same,  their 
combined  figures,  representing  the  corpuscles  found  in  a  space 
corresponding  to  7,200  of  the  small  ruled  squares,  is  taken  as  a 
basis  for  the  final  estimate ;  but  if  these  totals  widely  differ,  a 
4 


50         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

third  drop  is  to  be  examined  in  the  same  manner,  and,  as  in 
counting  the  erythrocytes,  an  average  taken  of  the  two  totals 
which  are  nearest  ahke.  Since  in  normal  blood,  in  a  i  :  200 
dilution  each  block  of  400  small  squares  contains  from  3  to  6 
leucocytes,  the  examination  of  the  above-mentioned  area  of  the 
counting  chamber  involves  the  counting  of  approximately  from 
54  to  108  of  these  cells — an  operation  which,  practically,  is  not 
nearly  so  laborious  as  it  appears  from  the  description,  being 
easily  completed  within  ten  or  fifteen  minutes,  in  most  cases/ 

As  an  example  of  the  method  of  calculating  the  final  estimate, 
supposing  that  90  leucocytes  have  been  counted  in  the  area  equal 
to  7,200  small  squares,  the  blood  dilution  being  i  :  200,  this  for- 
mula is  employed  : 

90  X  200  X  4,000  -i-  7,200  =  10,000  leucocytes  per  cb.  mm. 

If  the  old-style  counting  chamber  is  used,  the  leucocytes  in  the 
unruled  portion  of  the  disc  outside  of  the  central  block  of  400 
squares  may  be  counted  with  the  aid  of  an  eye -piece  diaphragm, 
which  when  adjusted  inside  the  tube  of  the  ocular  cuts  off  a  field 
exactly  the  size  of  100  small  squares  (Fig.  19).  A  black  metal 
or  cardboard  disc  having  a  central  aperture 
^^^-  ^9-  of  the  proper  size  will  answer  just  as  well  for 

this  purpose  as  the  more  expensive  and  elab- 
orate mechanical  eye-piece  devised  by  Ehrlich, 
which  is  provided  with  a  diaphragm  having  a 
square  opening  the  size  of  which  is  regulated 
by  a  small  lever.  Having  first  counted  all  the 
leucocytes  in  the  400  small  squares,  the  cells  are 
Ocular  diaphragm.  then  countcd  in  3  2  of  the  diaphragm-fields  out- 
side the  latter,  in  order  to  cover  an  area  of  the 
disc  corresponding  to  the  entire  ruled  surface  of  the  Zappert  count- 
ing chamber.  This  operation  having  been  repeated  in  a  second 
drop,  the  totals  of  both  counts  are  taken  as  the  basis  for  the  final 
calculation,  which  is  made  in  the  manner  already  described. 

If  one  happens  to  possess  neither  an  eye-piece  diaphragm  nor 
a  Zappert  counting  chamber,  the  following  method  of  calculat- 
ing the  cubic  contents  of  the  portions  of  the  disc  outside  the 
ruled  area  may  be  adopted,  as  advised  by  Stengel.^  Using,  for 
example,  a -^-inch  objective  and  a  i-inch  ocular,  the  ruled  lines 
are  brought  into  focus,  and  the  tube  of  the  microscope  drawn 
out  until  one  of  the  parallel  lines  of  the  ruled  disc  exactly  coin- 
cides with  either  boundary  of  the  field  of  vision.    Assuming  that  8  of 

1  Should  the  leucocytes  be  decidedly  increased,  it  is  unnecessary  to  cover  such  a 
large  number  of  squares.  One  hundred  cells  taken  as  a  basis  for  the  calculation  will 
give  an  accurate  estimate, 

^  "Twentieth  Century  Practice  of  Medicine,"  N.  Y.,  1896,  vol.  vii.,  p.  271. 


COUNTING    THE    ERYTHROCYTES    AND    THE    LEUCOCYTES.         5  I 

these  parallel  columns,  each  ^V  millimeter  in  width,  are  included 
in  the  visual  field,  the  diameter  of  the  latter  is  therefore  tPq  or  |- 
millimeter,  and  the  radius  one-half  of  this  figure,  -^-^  or  ^  milli- 
meter. The  area  of  the  field  may  then  be  readily  determined  by 
multiplying  the  square  of  its  radius  by  3. 141 6.  Its  cubic  contents 
are  obtained  by  also  multiplying  by  J-q  millimeter,  formula  being  : 

|-  X  3-  X  YQ  X  i.\/if\6  =. 012^66^,  cubic  contents  of  the  visual  field. 

Having  in  this  manner  ascertained  the  cubic  contents  of  each 
field  of  vision,  the  final  calculation  of  the  number  of  leucocytes 
to  the  cubic  millimeter  of  undiluted  blood  is  made  by  multiply- 
ing the  total  number  of  these  cells  found  in  a  definite  number  of 
fields  ( for  instance,  50)  by  the  degree  of  dilution  (  usually  i  :20o), 
and  by  then  dividing  by  the  cubic  contents  of  each  field  (.0125- 
664)  multiplied  by  the  number  of  fields  examined.  The  formula 
for  this  calculation  is  : 

(  Total  munber  of  leucocytes  counted  x  Degree  of  dilution  )  -r- 
( Cubic  contents  of  visual  field  x  Number  of  fields  examined  )  = 
Total  number  of  leucocytes  per  cb.  mm. 

For  example,  in  a  i  :  200  blood  dilution  a  total  of  30  leucocytes 
are  noted  in  50  fields,  each  having  a  cubic  contents  of  .0125664, 
since  they  individually  include  8  parallel  columns  of  the  ruled  disc  : 

(  30  X  200)  -^  (.0125664  X  50)  =  9,550  leucocytes  per  cb.  mm. 

{b)  If  the  special  leucocytometer  is  used  for  counting  the  leu- 
cocytes, a  0.3  per  cent,  aqueous  solution  of  glacial  acetic  acid 
must  be  employed  as  a  diluent,  in  order  to  render  invisible  the 
erythrocytes  and  at  the  same  time  to  make  the  leucocytes  appear 
more  conspicuously  in  the  field.  A  1:10  dilution  is  made,  by 
drawing  the  blood  up  the  capillary  tube  of  the  instrument  until 
the  mark  i  is  reached,  and  by  then  adding  the  diluent  until  the 
mixture  reaches  the  mark'  1 1.  The  leucocytes  are  then  counted 
in  an  area  of  the  counting  chamber  equal  to  800  of  the  small 
squares  (preferably  by  examining  400  squares  in  two  separate 
drops),  and  the  calculation  made  according  to  the  method  pre- 
viously described.  For  instance,  if  in  a  given  case  130  leucocytes 
were  counted  in  800  squares,  the  estimate  would  be  made  as  follows : 

130  X  4,000  X  10  -j-  800  =  6,500  leucocytes  per  cb.  mm. 

The  chief  objection  to  this  method  of  leucocyte  counting  lies 
in  the  difficulty  in  distinguishing  the  cells,  owing  to  the  unavoid- 
able presence  in  the  field  of  masses  of  granular  debris  resulting 
from  the  action  of  the  acetic  acid  solution  upon  the  erythrocytes. 
For  this  reason,  if  for  no  other,  it  seems  advisable  to  dispense 


52 


EXAMINATION    OF    THE    BLOOD    BV    CLINICAL    METHODS. 


with  the  leucocytometer,  and  to  make  the  count  of  both  red  and 
wliite  corpuscles  with  the  er}-throcytometer,  in  the  same  drop. 

Cleaning  the  Pipette,  As  soon  as  the  count  has  been  finished 
the  pipette  should  be  carefully  cleaned  and  dried.  Having  first 
expelled  what  remains  of  the  blood  dilution,  the  instrument  is 
nnscd  out,  first  with  distilled  water  and  then  with  a  mixture  of 
equal  parts  of  absolute  alcohol  and  ether,  the  latter  being  used  to 
remove  all  traces  of  the  dye,  in  case  either  Toisson's  or  Sherring- 
ton's solution  has  been  employed  as  a  diluent,  as  well  as  to  dry 
the  interior  of  the  tube.  The  pipette,  while  it  may  be  filled  with 
a  fluid  by  suction,  should  not  be  emptied  by  blowing  through  it, 
for  if  this  is  done  a  certain  amount  of  moisture  from  the  breath 
unavoidably  becomes  deposited  in  its  lumen.  Its  contents  may  be 
expelled  in  the  form  of  a  fine  jet,  simply  by  twisting  the  rubber  suc- 
tion tube  into  a  tight  spiral  rope,  as  shown  in  the  illustration  (Fig. 
20).     When  the  interior  of  the   instrument  is  perfectly  clean,  it 

Fig.  20. 


Expelling  contents  of  erythrocytometer. 

By  twisting  the  rubber  suction  tube  into  a  tight  spiral  rope,  the  fluid  in  the  bore  of  the  pipette  may  be 
.  forcibly  expelled  in  a  fine  jet. 


is  dried  by  forcing  through  it  a  current  of  air,  by  means  of  a 
rubber  atomizer  bulb,  or  an  ordinaiy  bicycle  pump,  until  the  glass 
bead  no  longer  clings  to  the  wall  of  the  bulbous  expansion,  as  it 
will  as  long  as  the  slightest  trace  of  moisture  remains.' 

A    new   form  of   hemocytometer    has    been 
recently  described  by  Durham,  who  has  em- 
bodied in  this  device  the  principles  of  the  older 
instruments,  together  with  the  substitution  of  a 
self-measuring  pipette  designed  to  overcome  the  sources  of  error 
which  may  occur  in  making  blood  dilutions  with  a  suction  pipette. 
Durham's  instrument,  which  appears  to  be  a  valuable  improve- 

^  A  o.  I  per  cent,  solution  of  pepsin  in  I  per  cent,  hydrochloric  acid  is  useful  for 
removing  any  bits  of  clotted  blood  which  may  adhere  to  the  caliber  of  the  instrument. 


Durham's  Hem 
ocvtometer. 


COUNTING    TIJE    ERYTHROC\TES    AND    THE    LEUCOCYTES.  53 

ment  over  other  forms  of  blood-counting  apparatus,  consists  of 
the  following  parts  : 

1 .  Several  capillary  pipettes,  of  the  Oliver  type,  each  mounted 
in  a  glass  tube,  pro\*ided  with  a  rubber  nipple  having  a  lateral 
perforation.  The  capacit}'  of  the  pipettes  is  of  5  and  10  cubic 
millimeters. 

2.  A  number  of  viixirig  vessels,  each  consisting  of  a  small  glass 
test-tube,  graduated  for  i  and  for  0.5  cubic  centimeters  of  fluid. 
The  tubes  holding  i  cubic  centimeter  measure  2|  x  -^^  inches, 
and  those  holding  0.5  cubic  centimeter,  2|- x  |  inches.  One  or 
more  glass  beads  are  shaken  about  in  the  tube,  to  mix  the  blood 
and  the  diluting  fluid. 

3.  A  number  of  graduated  pipettes,  for  measuring  the  diluting 
fluid,  of  I  and  0.5  cubic  centimeters  capacity,  marked  at  995  and 
990  cubic  millimeters,  and  at  495  and  490  cubic  millimeters, 
respectively.  Used  with  the  appropriate  capillar}-  pipette,  dilu- 
tions of  I  in  200,  I  in  100,  and  i  in  50  may  be  obtained. 

4.  A  counting  chamber  of  the  Thoma-Zeiss  pattern. 

Fig.  21. 


Cross  section  of  Durham's  blood-pipette. 

T,  glass  tube ;  N,  rubber  nipple ;  p,  lateral  perforation  in  nipple ;  c,  cork  in  which  a  capillary- 
pipette  is  fitted. 

Method  of  Use.  Having  placed  in  one  of  the  mixing  vessels 
some  of  the  diluting  fluid,  the  quantit}'  of  which  is  measured  with 
one  of  the  graduated  pipettes  according  to  the  dilution  desired,  the 
capillar}-  pipette  is  filled  with  blood,  by  touching  it  lightly  to  the 
blood  drop  as  it  flows  from  the  puncture.  All  traces  of  blood  are 
then  removed  from  the  outside  of  the  pipette,  the  contents  of  which 
are  now  expelled  into  the  fluid,  contained  in  the  mixing  vessel. 
This  is  accomplished  b\-  inserting  the  pipette  into  the  latter,  keep- 
ing its  point  about  half  an  inch  above  the  level  of  the  diluting  fluid, 
and  by  then  rotating  it  between  the  thumb  and  forefinger  so  that 
the  lateral  perforation  Is  brought  under  the  pulp  of  the  thumb ; 
the  nipple  is  now  squeezed  genth%  and,  continuing  the  pressure, 
the  pipette  is  rotated  back  so  that  the  perforation  is  free  again. 
In  this  manner  the  blood  is  forced  from  the  pipette,  but  is  not 
sucked  back.  The  blood  remaining  in  the  pipette  is  now  com- 
pletely washed  away  by  thrusting  its  point  into  the  diluting  fluid, 
this  at  once  filling  its  caliber,  by  capillarity.     Withdrawing  the 


54         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

pipette  from  the  fluid,  the  rotation  and  pressure  of  the  nipple  are 
repeated,  the  capillar}-  tube  being  thus  rinsed  out  several  times  in 
order  to  remove  completely  all  the  blood  clinging  to  its  interior. 

The  blood  and  the  diluting  fluid  are  now  mixed  by  briskly  ro- 
tating the  mixing  vessel  between  the  opposed  hands,  so  that  the 
tumbling  about  of  the  glass  beads  in  the  vessel  may  thoroughly 
distribute  the  cellular  elements  through  the  fluid.  When  the 
mixing  is  completed,  a  drop  of  the  fluid  is  transferred  to  the 
counting  chamber,  and  the  corpuscles  counted  under  the  micro- 
scope, in  the  usual  manner. 

Durham's  device  makes  it  possible  for  the  unskilled  to  measure 
accurately  the  desired  volumes  of  blood  and  diluting  fluid,  and 
largely  eliminates  the  errors  which  are  likely  to  occur  in  sucking 
up  the  blood  and  the  diluent  with  either  the  Thoma-Zeiss,  or 
the  Gowers  hemocytometer.  The  ease  and  thoroughness  with 
which  the  capillary  blood  pipette  may  be  cleaned  is  also  an  ad- 
vantage, this  being  done  by  passing  through  its  caliber  a  piece  of 
darning  cotton,  dr}'  or  soaked  in  ether,  by  means  of  a  needle. 
Comparative  obsen-ations  made  with  the  Thoma-Zeiss  hemocy- 
tometer have  shown  that  the  readings  of  the  two  instruments  are 
practically  identical. 

In  this  form  of  hemocytometer,  the  blood  and 
Gowers'  Hem-  the  diluting  fluid  are  each  measured  in  a  separate 
OCYTOMETER.  pipette,  and  deposited  in  a  small  receptacle  in 
which  they  are  mixed,  a  small  portion  of  the  mix- 
ture then  being  placed  in  a  counting  chamber  and  the  number  of 
corpuscles  counted  under  the  microscope.  Gowers  prefers  to  use 
as  a  diluent  an  aqueous  solution  of  sodium  sulphate  having  a 
specific  gravity  of  1025,  but  Toisson's  solution,  or  any  of  the 
other  diluting  fluids  prev^iously  mentioned  \\ill  prove  satisfactory'. 
The  instrument  comprises  five  working  parts,  as  follows  : 

1.  A  pipette,  graduated  to  hold  a  volume  of  995  cubic  milli- 
meters, for  measuring  the  diluting  fluid. 

2.  A  capillary  pipette,  graduated  to  hold  a  volume  of  5  cubic 
millimeters,  for  measuring  the  blood. 

3.  A  small  glass  i)iixi)ig  jar,\\\  which  the  dilution  of  the  blood 
is  made. 

4.  A  glass  stirring  rod,  for  mixing  the  blood  and  the  diluent 
in  the  jar. 

5.  A  counting  cJianiber,  consisting  of  a  glass  slide,  mounted  on 
a  brass  plate,  and  containing  a  cell  one-fifth  of  a  millimeter  in 
depth,  the  floor  of  the  cell  being  divided  by  cross  rulings  into 
squares  the  sides  of  which  measure  one-tenth  of  a  millimeter. 
When  a  cover-glass  is  fitted  over  this  cell,  being  retained  in  po- 


COUNTING  THE  ERYTHROCYTES  AND  THE  LEUCOCYTES.    55 

sition  by  means  of  a  pair  of  clips  attached  to  either  end  of  the 
brass  plate,  the  cubic  contents  of  the  space  overlying  each  square 
measure  1/500  of  a  cubic  millimeter. 

Method  of  Use.  In  using  the  instrument,  995  cubic  miUimeters 
of  the  diluting  solution  are  first  measured  by  means  of  the  larger 
pipette,  and  blown  out  into  the  mixing  jar.  The  latter  must  be 
perfectly  clean  and  absolutely  free  from  moisture  before  it  is  used, 
in  order  to  avoid  errors  in  the  count.  Now,  using  the  capillary 
blood  pipette,  5  cubic  millimeters  of  blood  are  secured  from  the 
puncture,  and  immediately  added  to  the  diluent  contained  in  the 
jar.  The  blood  and  the  diluent  are  then  thoroughly  mixed,  by 
rapidly  stirring  the  solution  with  the  glass  rod.  The  dilution  thus 
made  is  in  the  proportion  of  I  in  200  of  blood  to  diluent.  As 
soon  as  the  mixture  is  completed,  a  small  drop  of  the  solution  is 
transferred  to  the  center  of  the  cell  in  the  middle  of  the  counting 
chamber,  the  small  end  of  the  glass  rod  being  used  for  this  pur- 
pose, after  which  the  cover-glass  is  gently  placed  in  position,  and 
the  clips  adjusted  so  as  to  hold  it  in  place.  The  counting  cham- 
ber may  then  be  placed  upon  the  stage  of  the  microscope,  and 
the  corpuscles  overlying  the  ruled  portion  of  the  cell  brought 
into  focus  with  a  low-power  objective. 

It  is  necessary  to  use  a  small  drop  of  the  diluted  blood,  and 
to  place  it  exactly  in  the  center  of  the  block  of  ruled  squares, 
otherwise  the  fluid  may  flow  towards  the  walls  of  the  cell,  alter- 
ing its  volume,  and  making  it  necessary  to  reject  the  specimen, 
and  to  prepare  a  new  drop,  after  thoroughly  cleaning  and  drying 
the  cell,  and  again  stirring  the  blood  solution. 

The  corpuscles  having  settled  to  the  bottom  of  the  cell, 
their  number  in  a  given  number  of  squares  is  noted,  and  the 
final  calculation  made  according  to  the  formula  : 

Number  of  Ntimber  of         ^^^^^  ^^^^^^^^  ^jr  ^^^_ 

corpuscles    x  200  x  500  -     squares      =        ^^^^^^         ^^^  ^^^^^^ 
counted  counted 

In  counting  the  erythrocytes  at  least  20  squares  of  the  count- 
ing chamber  should  be  inspected,  in  different  drops,  a  procedure 
involving  the  enumeration  of  about  1,000  cells,  in  normal  blood. 
Except  in  high  leucocytoses,  the  number  of  leucocytes  is  usually 
estimated  indirectly,  by  determining  their  ratio  to  the  erythro- 
cytes, and  basing  their  actual  number  upon  this  figure.  This 
plan  (the  necessity  for  which  is  a  serious  drawback  to  the  use  of 
this  instrument)  is  followed  so  as  to  dispense  with  the  tedious 
filling  and  refilling  of  the  counting  chamber,  in  an  endeavor  to 
find  a  sufficient  number  of  leucocytes  to  serve  as  a  basis  for  the 


56  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

calculation,  should  the  latter  be  direct.  Ordinarily,  not  more 
than  two  of  these  cells  are  contained  in  an  area  including  20 
squares.  Gowers^  claims  that  the  limit  of  error  with  his  instru- 
ment is  less  than  3  per  cent. 

After  use,  the  different  parts  of  the  instrument  are  to  be  thor- 
oughly cleaned  and  dried,  in  the  manner  already  described. 

For  making  rapid  numerical  estimates  of  the 
Oliver's  Hem-  er\'throcvtes   Oliver   has  desig-ned  an  instrument 

OCVTOMETER.    based   upon  the  following  principles  :    When   a 
candle  flame  is  viewed  through  a  flat  Hass  test- 

o  o 

tube  filled  with  water,  a  bright  transverse  line  is  visible,  com- 
posed of  densely  packed,  minute  images  of  the  flame  produced 
by  the  longitudinal  corrugations  of  the  glass.  If  for  the  water  a 
mixture  of  blood  and  Hayem's  solution*  is  substituted,  a  more  or 
less  opaque  fluid  results,  so  that,  in  low  dilutions,  this  illuminated 
line  is  invisible,  reappearing  only  when  a  definite  degree  of  higher 
dilution  is  reached,  by  the  gradual  addition  of  the  diluent ;  when 
this  point  has  been  obtained,  the  line  is  again  detected  as  a  bright, 
delicate  streak  horizontally  crossing  the  tube.  Experiments 
having  proved  that  the  development  of  such  a  line,  by  gradual 
dilution  of  the  blood  with  Hayem's  fluid,  is  an  accurate  gauge  of 
the  percentage  of  erythrocytes  in  the  specimen  tested,  it  remained 
for  Oliver  to  devise  a  hemocytometer  consisting  of  the  following 
essential  parts  : 

1.  A  capillary  pipette,  for  measuring  the  blood. 

2.  A  glass  dropper,  one  end  of  which  is  capped  by  a  rubber 
nipple,  the  other  by  a  short  rubber  nozzle  which  fits  over  the 
blunt  end  of  the  pipette. 

3.  A  standard  gradiiated  tube,  in  which  the  blood  and  the 
diluent  are  mixed. 

The  four  walls  of  the  tube  are  flattened  so  that  it  is  rectangular 
on  cross-section,  one  wall  being  provided  with  an  etched  scale, 
indicating  units  from  10  to  120.  Each  of  these  divisions  is  equiv- 
alent to  50,000  erj-throcytes,  the  point  marked  100  degrees 
representing  the  arbitrar}'  normal  number,  5,000,000. 

Small-sized  wax  candles,  known  as  **  Christmas  candles,"  are 
to  be  preferred  for  the  illumination,  as  they  give  the  small  flame 
requisite  to  obtain  a  sharply  defined  line,  but  the  flame  from  a 
gas-jet  turned  low  may  also  be  used  with  satisfaction. 

Method  of  Use. —  In  making  the  observation  the  pipette,  which 
has  been  previously  cleaned  and  dried,  is  filled  with  blood  in  the 
usual  manner,  and  any  excess  of  blood  on  the  outside  carefully 

1  Lancet,  1877,  ^'o^-  "•»  P-  797- 
^  For  formula,  see  page  41 . 


COUNTING  THE  ERYTHROCYTES  AND  THE  LEUCOCYTES.    57 


22. 


removed.  The  rubber  nozzle  of  the  dropper,  filled  with  Hayem's 
fluid,  is  then  slipped  over  the  blunt  end  of  the  pipette,  and  the  blood 
washed  out  into  the  graduated  tube  by  squeezing  the  nipple. 
This  preliminary  dilution  is  continued  until  the  column  in  the 
tube  rises  to  within  lo  or  1 5  degrees  below  the  figure  for  the 
hemoglobin  percentage  of  the  same  blood,  this  having  been  pre- 
viously determined.  For  instance,  if  the  hemoglobin  percentage 
was  found  to  be  70,  the  diluting  fluid  is  added  in  large  quan- 
tities until  the  mixture  in  the  tube  reaches  to  about  the  mark  60, 
after  which  it  is  added  more  cautiously,  and  in  smaller  quantities 
at  a  time,  careful  search  for  the  bright  line  being  made  after  each 
addition.  In  cases  of  chlorosis  and  of  pernicious  anemia,  in 
which  parallelism  between  the  hemoglobin  and  corpuscular  loss 
is  lacking,  it  is,  of  course,  impossible  to  depend  upon  the  hemo- 
globin percentage  as  an  index  to  the  amount  of  diluent  required, 
so  that  in  instances  of  this  kind  the  line  must  be  developed  more 
slowly,  by  making  a  smaller  primary  dilution,  and  by  adding  the 
requisite  volume  of  liquid  more  deliberately. 

After  the  first  dropperful  of  diluent  has  been  added  to  the  con- 
tents of  the  tube,  the  latter  are  mixed  by  inverting  the  tube  a 
number  of  times  with 

the  thumb  held   over  Fig. 

its  mouth,  the  precau- 
tion being  taken  also 
to  remove  the  thumb 
by  drawing  it  over  the 
mouth  of  the  tube,  in 
order  to  restore  to  its 
contents  any  liquid 
which  may  have  ad- 
hered to  the  skin.  The 
tube  should  be  thus 
inverted  after  each  ad- 
dition of  the  diluting 
fluid. 

The  steps  of  the  ob- 
servation succeedine 
the  measuring  of  the 
blood  and  its  primary 
dilution  are  to  be  made  in  a  dark-room,  free  from  cross  lights, 
the  candle  being  placed  about  ten  feet  distant  from  the  observer. 
In  order  to  shut  out  the  diffused  light  of  the  candle,  the  tube 
should  be  held  vertically  in  the  concavity  formed  between  the 
thumb  and  forefinger,  the  tube  being  kept  close  to  the  eye  while 


Method  of  using  Oliver's  hemocytometer. 


Showing  manner  in  which  the  blood  is  washed  from  the  capil- 
lary pipette  into  the  tube  containing  Hayem's  solution. 


58  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

searching  for  the  bright  line.  OHver  states  that  the  earliest 
indications  of  this  line  are  obtained  by  turning  the  tube  on  its 
axis,  when  it  will  become  visible  at  the  sides  of  the  tube. 

It  is  claimed  that  tests  made  with  this  instrument  are  accurate 
within  one  per  cent.,  and  that  in  many  cases  it  may  be  used  as  a 
substitute  for  the  more  laborious  method  of  counting  the  cor- 
puscles under  the  microscope.  It  is  obv^ious,  however,  that,  apart 
from  the  "  personal  equation,"  the  serious  drawback  to  this  test 
is  its  failure  to  indicate  the  number  of  leucocytes,  this  fact  alone 
being  sufficient  to  curtail  its  use  for  routine  clinical  work.  It  is 
also  apparent  that  in  cases  of  marked  leucocytosis  and  of  leuke- 
mia the  optical  principles  of  the  test  must  necessarily  fail  because 
of  the  enormous  number  of  leucocytes  in  the  blood.  Further- 
more, it  is  reasonable  to  infer  that  the  instrument  will  give  false 
results  with  blood  in  which  conspicuous  deformities  of  the  er}-th- 
rocytes  exist,  for  the  reason  that  the  standard  tube  is  corrected 
for  normally  shaped  corpuscles,  so  that  blood  composed  largely 
of  microcytes,  or  megalocytes,  or  poikilocytes  will  give  different 
readings  from  blood  in  which  the  cells  are  of  unaltered  biconcave 
shape  and  of  normal  size. 


IV.     EXAMINATION   OF   THE   STAINED    SPECIMEN. 

The  microscopical  study  of  the  dried  and 
Objects  of  stained  blood-film,  which  should  supplement  the 
Staining.  methods  of  investigation  just  described,  is  for 
many  reasons  the  most  important  step  in  the 
clinical  examination  of  the  blood.  By  means  of  this  method 
of  "  color  analysis  "  it  is  possible  to  differentiate  easily  and  with 
absolute  certainty  the  various  forms  of  leucocytes  and,  by  differ- 
ential counting,  to  calculate  the  relative  percentages  of  each 
variety  of  these  cells  ;  to  distinguish  the  several  structural  de- 
generative changes  affecting  chiefly  the  erj'throcytes,  and  to  a 
less  extent  the  leucocxies  ;  and  to  recognize  and  classify  accord- 
ing to  their  histological  character  the  nucleated  forms  of  the  er}'th- 
rocytes.  To  sum  up,  in  the  words  of  Ehrlich,^  to  whom  we 
owe  this  rational  means  of  investigration  :  '*  Ever\-thin2:  that  is 
to  be  seen  in  the  fresh  specimens — apart  from  the  quite  unim- 
portant rouleaux  formation  and  ameboid  movements — can  be 
seen  equally  well,  and  indeed  much  better,  in  a  stained  prepara- 
tion ;  and  there  are  several  important  details  which  are  only  made 
visible  in  the  latter,  and  never  in  wet  preparations." 

^Ehrlich  and  Lazarus:   "Die  Anaemic,"    Wien,    1900.      (Nothnagel's  "Spec. 
Path.  u.  Therap.,"  vol.  viii.,  n.  2.) 


EXAMINATION    OF    THE    STAINED    SPECIMEN. 


59 


According    to    the    classification     introduced 
The  Aniline  twenty  years  ago  by  Ehrlich/  the  aniline  dyes 
Dyes.  are   divided  into    three    different  groups  :    acid, 

basic,  and  neutral.  Acid  dyes,  or  compounds  in 
which  the  coloring  principle  acts  or  exists  as  an  acid,  possess  a 
special  affinity  for  cell  protoplasm,  and,  therefore,  are  generally 
employed  as  plasma  stains  ;  in  hematological  work  acid  fuchsin, 
eosin,  and  orange  G  are  the  principal  dyes  used  for  this  purpose. 
Basic  dyes,  or  compounds  in  which  the  coloring  principle  exists 
chemically  as  a  base  in  combination  with  a  colorless  acid,  are 
especially  useful  as  nuclear  stains,  since  they  exhibit  a  special 
affinity  for  chromatin  structures ;  members  of  this  group  of 
dyes  commonly  used  in  blood  staining  are  methylene-blue,  tol- 
uidin-blue,  methyl-green,  methyl -violet,  thionin,  and  hema- 
toxylin. Neutral  dyes  are  the  coloring  principles  which  re- 
sult from  the  mixture  of  solutions  of  an  acid  and  a  basic  dye  ; 
they  are  used  for  the  demonstration  of  the  so-called  neutro- 
phile  granules  of  the  leucocytes,  for  which  they  show  a  selective 
affinity. 

For  the  preparation  of  the  dried  blood-films  it 

Preparing      is  advisable  to  have  at  hand  at  least  half  a  dozen 

THE  Films,      perfectly    clean,    polished    cover-glasses,    which 

may  be   arranged  in   pairs  on  a   sheet  of  white 

paper  within  convenient  reach   of  the  examiner.     After  having 

wiped  away  the  blood  which  immediately  follows  the  puncture,  a 

minute   portion    of    the    next 

drop  is    collected,   by  lightly  ^^'  ^^' 

touching  the  center  of  one  of 
the  cover-glasses  to  its  sum- 
mit, care  being  taken  to  avoid 
bringing  the  polished  surface 
of  the  glass  in  contact  with 
the  skin  of  the  patient's  finger. 
The  charged  cover-glass  is 
then  at  once  dropped,  blood 

.  ,        ,  .'■'■.  I.  Superimposing  the  charged  cover-glass. 

Side  downward,  upon  the  sur- 
face of  the  second  glass  (Fig.  23),  with  the  result  that  the 
blood  quickly  spreads  out  in  a  thin  film  between  the  two,  and  ex- 
tends to  their  peripheries,  provided  that  the  proper  quantity  of  blood 
has  been  used.  (Fig.  24.)  As  soon  as  the  film  has  reached  the 
margins  of  both  cover-glasses,  they  are  rapidly  drawn  apart  in  a 
horizontal  direction,  so  that  the  surface  of  each,  when  thus 
-separated,  is  covered  with  a  thin  layer  of  blood  (Fig.  25),  which 
^Zeitschr.  f.  klin.  Med.,  i88o,  vol.  i.,  p.  555. 


6o 


EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 


Dra\ving  apart  the  coyer-glasses. 


Fig. 


should  be  rapidly  dried,  either  by  blowing  briskly  upon  its  sur- 
face, or  by  holding  the  glass  for  a  few  seconds  high  over  the 
flame  of  an  alcohol  lamp.     If  care  is  taken  to   use  but  a  ver}' 

small  drop  of  blood,  to  avoid 
^^^-  ^4-  pressure  in  opposing  the  sur- 

faces of  the  two  cover-g-lasses, 
and  to  separate  them  in  their 
true  horizontal  planes,  the 
films  will  consist  of  a  single 
layer  of  corpuscles,  most  of 
which  will,  be  sufficiently  iso- 
lated to  allow  the  study  of 
their  individual  morphology^ 
and  other  characteristics.  The 
beginner  should  persistently 
practice  the  technique  of  film  making  until  he  is  able  to  obtain 
a  satisfactor}'  percentage  of  good  specimens  from  ever}*  batch 
of  spreads.  Thick,  uneven  spreads,  in  which  the  corpuscles  are 
heaped  up  and  glued  together  in  dense  masses,  are  practically 
of  no  value  for  microscopical  study ;  such  specimens  should 
therefore  be  rejected  at 
once,  since  it  is  time  wasted 
to  attempt  satisfactorily  to 
stain  them. 

The  films,  after  having 
been  dried,  may  be  placed 
in  a  pill  box,  and  labelled, 
to  await  fixation  and  stain- 
ing at  the  examiner's  con- 
venience. .  Dried  specimens 

will  keep  for  an  indefinite  period,  if  not  exposed  to  dust  or  to 
moisture.  Unfixed  cover-glass  specimens  of  leukemic  blood 
have  been  stained  by  the  writer,  with  perfect  results,  more  than 
three  years  after  they  were  spread. 

Many  histologists  recommend  the  use  of  special  forceps  for  hold- 
ing the  cover-glasses  while  making  the  spreads,  claiming  thus  to 
avoid  the  injurious  effects  upon  the  blood  corpuscles  which  may 
be  caused  by  the  moisture  of  the  fingers,  if  the  latter  come  in 
contact  with  the  films.  The  careful  worker  need  have  no  fear  on 
this  score,  for  if  the  covers  are  held  in  the  manner  shown  in  the 
illustrations  this  accident  will  not  occur.  A  pair  of  light  thumb 
forceps  is  useful  for  picking  up  the  cover-glasses  from  a  flat  sur- 
face, but  the  employment  of  special  spreading  forceps  is  quite 
superfluous. 


The  cover-glasses  after  separation. 


EXAMINATION    OF    THE    STAINED    SPECIMEN. 


6l 


Fig.   26. 


As  a  step  preliminary  to  staining,  the  albumi- 

FiXATiON       noid  principles  of  the  blood  must  be  fixed,  by  ex- 

Methods,      posing  the  dried  film  either  to  a  high  degree  of 

dry  heat,  or  to  various  chemical  hardening  agents, 

the  choice  between  these  two  methods  being  determined  by  the 

character  of  the  staining  solution  to  be  used  subsequently. 

Heat  Fixation.  This  method  may  be  employed  with  any  of 
the  stains  described  in  the  following  pages  ;  it  must  be  used  with 
Ehrlich's  triple  stain,  in  preference  to  fixation  by  chemicals,  in 
order  to  obtain  crisp,  clean-cut  pictures. 

The  author  is  accustomed  to  use  an  oven,  such  as  is  illustrated 
below  (Fig.  26),  consisting  of  a  copper  box  with  a  heavy  bottom, 
and  hinged  cover,  mounted  on  an 
ordinary  iron  burette  stand,  by 
means  of  a  thumb-screw.  A  small 
**  baby"  Bunsen  lamp  placed  under- 
neath the  box  furnishes  the  requi- 
site degree  of  heat,  the  temperature 
being  indicated  by  a  thermometer 
mounted  at  one  end,  and  resting 
upon  the  floor  of  the  oven.  By 
sliding  the  latter  up  and  down  the 
vertical  rod  to  which  it  is  attached, 
the  desired  degree  of  temperature 
may  be  obtained  at  will.  The  blood- 
films  are  enclosed  in  the  copper 
box,  and  the  latter  fixed  at  a  point 
eight  inches  above  the  summit  of 
the  burner,  after  which  the  gas  is 
lighted  and  allowed  to  burn  until 
the  temperature,  as  indicated  by  the 
thermometer,   has   gradually   crept 

up  to  160°  C.  As  soon  as  this  degree  of  heat  has  been  reached, 
the  gas  is  extinguished,  the  cover  of  the  oven  thrown  back,  and, 
after  the  temperature  has  fallen  to  30°  C,  the  films  removed, 
being  now  thoroughly  fixed,  and  ready  for  staining.  Fifteen 
minutes  suffice  for  the  whole  operation,  from  the  time  the  gas  is 
lighted,  until  the  films  have  been  removed  and  cooled,  for  staining. 
A  less  satisfactoiy  method  of  heat  fixation  is  by  the  use  of  a 
copper  plate  upon  which  the  films  are  kept  at  a  temperature  of 
from  100°  to  110°  C,  for  from  one-half  to  one  hour.  The  ap- 
.paratus  used  for  this  purpose  consists  of  a  rectangular  plate  of 
sheet  copper,  about  fifteen  inches  long,  by  four  inches  wide,  by 
one-sixth  of  an  inch  thick.     An  alcohol  or  a  Bunsen  lamp  bums 


Oven  for  fixing  blood-films. 


62  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

under  one  end  of  the  plate,  which  is  elevated  about  six  inches 
above  the  flame,  by  four  metal  legs.  After  having  heated  the 
plate  for  ten  or  fifteen  minutes,  until  a  relatively  constant  tem- 
perature becomes  established,  water  is  dropped  upon  its  surface, 
beginning  with  the  end  farthest  from  the  flame,  until  a  point  is 
reached  at  which  the  water  boils.  This  part  of  the  plate  is  con- 
sidered to  have  a  temperature  of  ioo°  C,  and  at  this  point  the 
blood-films  are  placed,  "  spread"  side  downward,  and  heated  for 
the  required  time.  No  one  with  much  blood  staining  to  do  will 
choose  this  method  of  prolonged  heating  at  a  relatively  low,  ap- 
proximate temperature  in  preference  to  brief  heating  at  a  high, 
definite  temperature  in  an  oven.  The  use  of  the  latter,  aside 
from  its  convenience  as  a  time-saver,  insures  constant  and  cer- 
tain results,  for  over-  and  underheating  of  the  blood-film  may 
be  avoided,  since  the  degree  of  heat  is  exactly  indicated  and  easily 
controllable.  In  triple  stained  specimens  the  blood  cells  are  much 
more  brilliantly  colored  and  sharply  differentiated  when  the  films 
are  fixed  at  a  temperature  of  i6o°  C,  than  at  a  lower  degree. 

Should  nothing  but  a  Bunsen  or  an  alcohol  lamp  be  available, 
the  cover-glass  film,  held  with  a  pair  of  forceps,  may  be  fixed  by 
passing  it  rapidly  through  the  flame  thirty  or  forty  times  and  then 
holding  it  twelve  or  fifteen  inches  above  the  flame  for  a  minute 
or  so.  This  makeshift  method,  which  is  often  sufficient  for  a  hur- 
ried clinical  examination,  usually  gives  fair,  and  sometimes  v^ery 
good,  results,  but  the  fixation  is  generally  uneven,  and  the  speci- 
men is  frequently  scorched  in  some  places  and  underfixed  in 
others. 

Chemical  Fixation.  Immersion  of  the  dried  films  in  ether,  in 
absolute  alcohol,  or  in  a  mixture  of  equal  parts  of  the  two  (Niki- 
foroff's  method)  gives  satisfactory  results  with  specimens  stained 
by  any  of  the  single  basic  dyes,  or  with  the  simpler  double  stains, 
such  as  eosin  and  methylene-blue  or  hematoxylin.  The  time  of 
fixation  varies  from  five  to  fifteen  minutes  with  any  of  these  agents, 
the  specimen  then  being  dried  without  using  heat,  and  stained 
without  previously  washing.  If  time  is  an  object,  the  specimens 
may  be  boiled  for  one  minute  in  a  test-tube  containing  absolute 
alcohol,  as  advised  by  Ehrlich.^  Some  workers  employ  one 
minute's  fixation  by  a  one  per  cent,  alcoholic  solution  of  forma- 
lin (Benario's  method),  while  others  prefer  to  expose  the  films  to 
the  vapors  of  this  chemical  for  the  same  length  of  time.  Solley  - 
has  recently  suggested  that  the  film  be  flooded  with  a  two  per  cent. 

^  Loc.  cit. 

2  Med.  and  Surg.  Reports  of  the  Presbyterian  Hospital,  N.  V.,   1900,  vol.  iv.,  p. 
169. 


EXAMINATION    OF    THE    STAINED    SPECIMEN.  63 

aqueous  solution  of  chromic  acid,  which  is  washed  off  after  exactly 
thirty  seconds,  the  specimen  being  then  stained,  while  still  wet ; 
he  recommends  this  procedure  as  a  substitute  for  heat  in  fixing 
specimens  for  triple  staining,  but  the  method,  while  fairly  good, 
cannot  be  regarded  as  entirely  satisfactory.  In  the  author's  hands 
a  two  per  cent,  aqueous  solution  of  osmic  acid  has  been  found  to 
be  the  best  substitute  for  heat  fixation. 

In  hematological,  as  in  other  histological  work 
Methods  of    the  choice  of  a  staining  method  is  determined  by 

Staining.  the  character  of  the  investigation  to  be  undertaken. 
For  general  clinical  purposes  it  is  advantageous 
habitually  to  employ  some  routine  method  by  means  of  which 
the  greatest  possible  number  of  elements  may  be  demonstrated 
in  a  single  blood-film,  this  procedure  being  known  as  panoptic 
staining.  Thus,  by  using  a  solution  containing  several  of  the 
aniline  dyes  the  stroma  of  the  erythrocytes,  the  cell-granules,  the 
cell-nuclei,  and  the  various  blood  parasites  may  be  simultaneously 
stained  each  in  a  characteristic  manner,  owing  to  the  selective 
affinity  displayed  by  the  different  coloring  principles  of  the  mix- 
ture towards  these  several  histological  elements.  The  most  useful 
solutions  which  have  been  devised  for  this  purpose  are  the  triacid 
mixture  of  Ehrlich,^  which  has  long  served  as  the  standard  stain 
for  hematological  investigation,  and  the  methylene -blue  eosinate 
solution  suggested  by  Jenner.^  Practically  all  the  information 
that  it  is  possible  to  derive  from  the  study  of  the  stained  dry 
blood-film  may  be  obtained  with  the  aid  of  these  two  solutions. 

Combinations  of  an  acid  and  a  basic  dye,  such  as  eosin  and 
methylene-blue,  eosin  and  hematoxylin,  and  orange  and  hema- 
toxylin are  used  by  many  investigators,  chiefly  for  the  purpose 
of  staining  the  cell-stroma  and  the  nuclear  structures  ;  but,  as  a 
general  rule,  such  mixtures  are  not  adapted  for  clinical  work, 
since  with  none  of  them  is  it  possible  to  differentiate  the  neutro- 
phile  granules.  Solutions  of  a  single  dye  are  but  seldom  used 
except  for  the  demonstration  of  special  elements,  such,  for  in- 
stance, as  the  staining  of  the  malarial  parasite  by  thionin,  the 
mast-cells  by  dahlia,  and  certain  bacteria  by  the  basic  dyes,  such 
as  methylene-blue  and  gentian-violet.  Since  by  this  method  of 
staining  only  the  particular  elements  toward  which  the  dye  reacts 
are  differentiated,  the  employment  of  single  stains  is  inadequate 
for  the  study  of  the  general  morphology  of  the  blood  cells. 

The  following  formulae  will  be  found  sufficient  for  all  purposes 
of  clinical  investigation  : 

1  Loc.  cit. 

2  Lancet,  1899,  vol.  i.,  p.  370. 


64  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

Ehrlich's  Triacid  Stain.  This  valuable  triple  stain,  con- 
taining one  basic  and  two  acid  dyes  (methyl-green,  orange  G, 
and  acid  fuchsin),  is  peculiar  in  that  a  chemical  combination  is 
formed  by  its  acid  and  basic  components  which  may  be  regarded 
as  a  neutral  coloring  principle,  serving  the  purpose  of  selectively 
staining  the  so-called  neutrophile  elements  for  which  the  primar>^ 
components  of  the  mixture  have  no  affinity.  With  this  stain  his- 
tological structures  having  an  affinity  for  the  acid  dyes  are 
stained  the  color  of  one  of  its  acid  constituents,  basic  structures 
the  color  of  its  basic  dye,  and  structures  having  an  equal  affinity 
for  acid  and  basic  dyes  the  color  of  the  neutral  compound. 

Saturated  aqueous  solutions  of  the  three  dyes  are  first  pre- 
pared, and  allowed  to  stand  for  several  days  until  they  have 
become  thoroughly  cleared.  It  is  essential  that  the  aniline  dyes 
used  for  making  these  "  stock  "  solutions  should  be  chemically 
pure,  to  ensure  which  the  products  of  Griibler,  or  of  the  Berlin 
Aniline  Dye  Company  should  invariably  be  chosen.  From  these 
saturated  solutions  the  following  mixture  is  made  : 

Acid  fuchsin  solution 6-   7  cc. 

Orange  G  solution 13-14  cc. 

Distilled  water 15         cc. 

Absolute  alcohol 15         cc. 

Mix  the  above  thoroughly,  and  add,  drop  by  drop, 
with  continuous  agitation,  in  the  following  order : 

Methyl -green  solution 12.5  cc. 

Absolute  alcohol 10      cc. 

Glycerine 10      cc. 

The  mixture  should  under  no  circumstance  be  filtered,  but  al- 
lowed to  stand  for  about  twenty-four  hours  in  order  that  a  slight 
precipitate  may  form.  As  soon  as  this  occurs  the  stain  is  ready 
for  use,  the  necessar}'  quantity  being  pipetted  from  the  super- 
natant fluid  without  disturbing  the  precipitate. 

Technique  of  Staining.  The  heat-fixed  film,  held  preferably 
with  a  pair  of  Stewart's  staining  forceps,  is  flooded  with  the  stain, 
which  is  washed  off  in  running  water  after  the  lapse  of  from  five 
to  eight  minutes,  the  specimen  then  being  dried  by  gentle  heat, 
and  mounted  in  xylol  balsam,  or  in  cedar-oil. 

In  the  specimen  thus  prepared  the  stroma  of  the  er\throcytes  is 
stained  orange,  the  nuclei  of  the  leucocytes  greenish-blue,  the"  neu- 
trophile granules  violet  or  lavender,  and  the  eosinophile  granules 
copper  red.  The  nuclei  of  the  erythroblasts  react  with  var>^ing 
degrees  of  intensity  toward  the  basic  component  of  the  mixture, 
those  of  the  normoblasts  staining  deep  purple  or  black,  and  those 
of  the  megaloblasts  pale  green  or  greenish-blue.     The  basophile 


EXAMINATION    OF   THE   STAINED    SPECIMEN.  65 

granules  remain  unstained,  appearing  as  dull  white,  coarse, 
stippled  areas  in  the  cell-protoplasm — ''negative  staining."  In 
order  to  stain  these  granules,  as  well  as  the  basic  protoplasm  of 
the  lymphocytes,  Hewes  ^  suggests  that  the  triple  stained  film, 
after  having  been  washed,  be  subjected  for  from  one-half  second 
to  ten  seconds  to  Loffler's  ^  methylene-blue  solution,  after  which  it 
is  again  washed,  and  mounted  as  above  directed.  This  modifica- 
tion is  of  undoubted  value,  chiefly  because  it  usually  enables  one 
to  differentiate  the  larger  forms  of  lymphocytes  from  the  large 
mononuclear  leucocytes.  Malarial  parasites,  and  bacteria  are 
also  distinctly  stained  by  this  method. 

Unsatisfactory  results  with  the  triple  stain,  provided  that  the 
latter  is  properly  made,  can  almost  always  be  attributed  to  faulty 
fixation.  As  already  remarked,  heat  is  the  only  method  of  fixa- 
tion which  will  insure  faultless  differentiation  in  the  specimen 
stained  with  this  mixture.  The  perfect  specimen  is  of  a  deep, 
rich  orange  tint  to  the  naked  eye  ;  if  underheated,  the  film  reacts 
too  strongly  toward  the  acid  fuchsin  of  the  mixture,  and,  conse- 
quently, is  the  color  of  this  dye  ;  if  overheated,  the  plasma 
stain,  orange  G,  is  but  feebly  displayed,  so  that  the  color  of  the 
film  is  pale  lemon  yellow.^ 

Jenner's  Stain.     This  solution,  made  by  dissolving  in  methyl 
alcohol  the  neutral  precipitate  obtained  by  the  addition  of  methyl- 
ene-blue to  eosin,  is  especially  valuable  in  the  study  of  the  lym- 
.phocytes,  and  the  mast-cells.     It  should  be   made  according  to 
the  following  somewhat  compHcated  formula : 

(a)  Eosin  (aqueous) 1.25  grm. 

Distilled  water 100        cc. 

(^)  Methylene-blue  (medicinal) i.o    grm. 

Distilled  water 100        cc. 

Equal  parts  of  these  two  solutions,  "a"  and  *'b,"  are  mixed 
together,  stirred  thoroughly  with  a  glass  rod,  and  set  aside  for 
twenty-four  hours,  so  that  complete  precipitation  may  occur.  In 
making  this  mixture,  the  methylene-blue  solution  should  be  added 
to  the  eosin  solution  (never  vice-versa)  in  small  quantities  at  a 
time,  the  fluid  being  constantly  stirred  during  the  addition.  A 
burette  with  the  stop-cock  regulated  so  as  to  deliver  the  former 
dye-solution,  drop  by  drop,  in  rapid  succession,  will  prove  useful 
to  insure  the  slow  admixture  of  the  two  fluids.     The  precipitate 

^  Boston  Med.  and  Surg.  Journ.,  1899,  vol.  cxli.,  p.  39. 

2  Saturated  alcoholic  solution  of  methylene-blue,  30  cc;  1-10,000  aqueous  solution 
of  potassium  hydrate,  loo  cc. 

3  A  reliable  triacid  stain,  made  according  to  Ehrlich's  formula,  is  sold  by  Messrs. 
Shinn  and  Baer,  Philadelphia. 

5 


66         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

is  collected  by  filtration,  dried  in  an  incubator,  at  a  temperature 
of  55°  C,  and  powdered  in  a  mortar.  The  powder  should  then 
be  washed,  by  shaking  it  up  with  distilled  water,  and  filtering, 
after  which  it  is  allowed  to  dry  in  the  air,  and  kept  in  a  tightly 
corked  bottle.  The  mixture  used  for  staining  is  made  by  dis- 
solving 0.5  grm.  of  this  powder  in  loocc.  of  pure  methyl  alcohol 
(Merck),  and  filtering. 

Technique  of  Staining.  Owing  to  the  methyl  alcohol  which 
it  contains,  Jenner's  solution  fixes  and  stains  the  blood-film 
simultaneously,  so  that  preliminary  fixation  may  be  omitted. 
The  unfixed  specimen  is  stained  for  from  three  to  five  minutes, 
washed  in  water  until  the  film  is  of  a  rose-red  color,  dried  in  air, 
and  mounted  in  the  usual  manner.  Since  the  solution  is  of  an 
exceedingly  volatile  character,  as  much  of  it  should  be  used  as 
can  be  placed  on  the  cover-glass  without  spilling  ;  if  this  is  not 
done,  the  specimen  may  be  ruined,  owing  to  the  rapid  evapora- 
tion of  the  stain  around  the  margins  of  the  cover-glass. 

Jenner's  stain  gives  the  following  results  :  erythroc}i:es,  terra 
cotta;  nuclei  of  the  leucocytes,  pale  sea-green;  neutrophile 
granules,  pale  pink  ;  eosinophile  granules,  deep  pink  ;  fine  baso- 
phile  granules,  deep  blue  ;  and  coarse,  mast-cell  granules,  deep 
royal  purple.  The  nuclei  of  the  erythroblasts,  and  the  blood 
parasites  stain  various  shades  of  bluish-green,  and  the  pseudo- 
granular  protoplasm  of  the  lymphocytes,  blue. 

The  chief  defect  in  Jenner's  stain  is  the  occasional  presence  of 
a  coarse,  granular  precipitate  which  mars  the  appearance  of  an 
otherwise  perfect  specimen.  If,  however,  the  precaution  is  ob- 
served always  to  filter  the  stain  before  use,  and  to  dry  the  film 
in  air — not  by  holding  it  over  a  Bunsen  flame — this  accident  may 
generally  be  avoided.  Aside  from  its  obvious  value  as  a  panop- 
tic staining  fluid,  this  solution  will  often  prove  of  great  convenience 
for  the  reason  that  it  does  not  require  special  fixation  of  the  blood- 
film. 

Prince's  Stain.  This  mixture,  which  consists  of  an  aqueous 
solution  of  one  basic  and  two  acid  dyes,  is  an  excellent  stain  for 
the  differentiation  of  both  nuclei  and  granules,  and  may  be  em- 
ployed as  a  fair  substitute  for  either  of  the  two  preceding  solutions. 
It  should  be  made  in  this  manner : 

Saturated  aqueous  solution  of  toluidin-blue 24  cc. 

Saturated  aqueous  solution  of  acid  fuchsin i  cc. 

2  percent,  aqueous  solution  of  eosin 2  cc. 

These  solutions  are  mixed  in  the  order  named,  and  shaken 
briskly  for  several  minutes,  so  as  to  secure  complete  precipitation 


EXAMINATION    OF    THE   STAINED    SPECIMEN.  6/ 

of  the  basic  toluidin-blue  by  the  acid  dyes.  The  solution,  which 
should  not  be  filtered,  is  ready  for  use  as  soon  as  made.  Only 
the  supernatant  fluid  should  be  employed,  care  being  taken  not 
to  disturb  the  sediment. 

Technique  of  Staining.  If  a  newly  made  solution  is  used,  the 
films  are  stained  for  from  one-half  to  one  minute,  after  which  they 
are  rinsed  in  water,  dried  in  air,  and  mounted  ;  but  if  the  solution 
has  stood  for  several  weeks,  its  basic  constituent  becomes  less 
active,  so  that  the  specimen  requires  to  be  stained  for  from  five  to 
ten  minutes.  Either  chemical  or  heat  fixation  of  the  blood-film 
may  be  used  with  this  stain,  both  methods  giving  equally  sharp  dif- 
ferentiation. Prince's  solution  colors  the  erythrocytes  rose-red,  the 
nuclei  of  the  leucocytes  and  erythroblasts  blue,  the  neutrophile 
granules  pink,  the  eosinophile  granules  maroon,  and  the  fine  and 
coarse  basophile  granules  blue.  Blood  parasites  are  also  stained 
the  color  of  the  basic  dye. 

Double  Staining  with  Eosin  and  Methylene-blue.  Crisp, 
clear  pictures  of  nuclear  and  stroma  structures,  of  the  ma- 
larial parasites,  and  of  the  basophile  granules  may  be  obtained 
be  the  use  of  these  two  dyes,  and  to  investigations  of  this  nature 
should  this  staining  method  be  restricted.  It  is  impossible,  for 
example,  accurately  to  distinguish  a  large  lymphocyte  from  a 
myelocyte  in  a  specimen  stained  in  this  manner,  so  that  for  differ- 
ential counting  a  more  elaborate  stain  is  essential.  In  films  stained 
by  this  method  the  stroma  of  the  erythrocytes  and  the  eosinophile 
granules  react  toward  the  acid  dye,  staining  the  color  of  eosin ; 
while  the  nuclei  of  the  leucocytes  and  erythrocytes,  the  basophile 
granules,  and  all  blood  parasites  show  art  affinity  for  the  basic 
dye,  being  colored  various  shades  of  blue.  The  protoplasm  of 
the  polynuclear  neutrophiles  is  either  colorless  or  tinged  a  deli- 
cate pink,  the  granules  of  these  cells  remaining  unstained. 

The  author  has  always  found  the  following  simple  formula  de- 
pendable : 

Eosin  (aqueous),  to  which  sufficient  water  has 

been  added  for  solution 0.5  grm. 

Absolute  alcohol 0.5  cc. 

Saturated  aqueous  solution  of  methylene-blue.. 96.0  cc. 

Technique  of  Staining.  Films  are  fixed  by  immersion  for  ten 
minutes  in  absolute  alcohol,  or  in  equal  parts  of  absolute  alcohol 
and  ether.  The  cover-glass  is  flooded  with  the  stain,  gently 
heated  for  one  minute  over  a  Bunsen  flame,  allowed  to  stain 
without  heat  for  two  or  three  minutes  longer,  and  then  thoroughly 
washed  in  running  water,  dried  in  air,  and  mounted. 


68  EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

Another  method  of  staining  with  eosin  and  methylene-blue, 
slower  than  the  above,  but  as  a  rule  giving  sharper  differentiation, 
is  to  stain  without  heat  for  five  minutes  with  a  0.5  per  cent,  solu- 
tion of  eosin  in  absolute  alcohol  to  which  an  equal  quantity  of 
water  is  added.  Then,  after  having  washed  off  the  eosin  solution 
and  dried  the  film  in  air,  the  specimen  is  counterstained  for  one 
minute  or  less  with  a  saturated  aqueous  solution  of  methylene- 
blue,  after  which  it  is  rinsed  again  in  water,  dried  in  air,  and 
mounted. 

Among  the  many  other  methods  of  staining  with  eosin  and 
methylene-blue,  those  suggested  by  Chenzinsky/  by  Plehn,-  and 
by  Holmes^  will  be  found  the  most  useful. 

Double  Staining  with  Eosin  and  Hematoxylin.  By  the  em- 
ployment of  these  two  dyes  the  erythrocytes  and  the  eosinophile 
granules  are  stained  the  color  of  eosin,  and  all  nuclei  and  parasites, 
the  color  of  hematoxylin.  This  method,  which  is  decidedly  in- 
ferior to  staining  with  the  eosin  and  methylene-blue  mixtures  just 
described,  is  useful  for  little  else  than  the  study  of  nuclear  struc- 
tures. It  should  not  be  used  for  differential  counting,  since  in 
films  stained  in  this  manner  the  neutrophile  granules  are  invisible. 
EhrHch*  recommends  this  formula  : 

Eosin   (cryst.) 0.5  grm. 

Hematoxylin 2.0  grm. 

Absolute  alcohol  100. o  cc. 

Distilled  water 100. o  cc. 

Glycerine 100. o  cc. 

Glacial  acetic  acid lo.o  cc. 

Alum  in  excess. 

This  mixture  must  '*  age  "  for  several  weeks  before  it 
can  be  used  for  staining. 

Technique  of  Staining.  Specimens,  fixed  either  chemically  or 
by  heat,  are  stained  for  from  one-half  hour  to  two  hours,  thor- 
oughly washed  in  water,  dried  and  mounted.  In  order  to  obtain 
the  best  results,  it  is  advisable  to  filter  the  solution  before  using, 
and  to  wash  the  films  ver>^  thoroughly  after  staining. 

If  time  is  an  object,  the  following  rapid  method  may  be  substi- 
tuted for  the  above  :  The  film  is  first  stained  for  about  five 
minutes  with  a  0.5  per  cent,  solution  of  aqueous  eosin  in  fifty  per 
cent,  alcohol,  washed,  and  dried  in  air ;  it  is  then  counterstained 

•  Zeitschr.  f.  wiss.  Mik.,  1894,  vol.  xi,,  p.  260. 

2  "  Aetiologische  und  klinische  Malaria  Studien,"  Berlin,  1890. 
'Joum.  Am.  Med.  Asso.,  1898,  vol.  xxx.,  p.  303. 

*  Loc.  cit. 


EXAMINATION    OF    THE   STAINED    SPECIMEN.  69 

for  about  one-half  minute  with  Delafield's  hematoxylin,^  washed 
for  a  second  time,  and  mounted  in  the  usual  manner. 

Staining  with  Thionin.  Thionin  (also  known  as  the  "violet 
of  Hoyer,"  and  the  ''violet  of  Lauth "  )  is  an  excellent  stain 
for  blood  parasites  in  general,  being  especially  useful  for  the 
demonstration  of  the  malarial  parasites  and  the  filarial  embryos. 
Thionin  should  not  be  used  as  a  stain  for  films  in  which  the  gen- 
eral morphology  of  the  blood  cells  is  to  be  studied,  since  the  baso- 
phile  granules  and  the  nuclei  are  the  only  histological  elements 
for  which  it  displays  any  decided  affinity.  Structures  reacting 
toward  the  dye  are  stained  violet  of  varying  degrees  of  intensity. 
The  following  recipe,  suggested  by  Futcher  and  Lazear,^  will 
prove  satisfactory  : — 

Thionin  0.3  grm. 

Absolute  alcohol 10. o  cc. 

I  per   cent,  solution    of  carbolic 

acid  q.  s.  ad 100. o  cc. 

Technique  of  Staijtmg.  Films  which  have  been  fixed  either 
chemically  or  by  heat  are  stained  in  the  above  solution  for  from 
one  to  three  minutes,  being  then  washed  in  water,  dried,  and 
mounted  as  usual.  The  best  results  are  obtained  by  using  the 
French  thionin,  made  by  Cogit  et  Cie,  of  Paris. 

Staining  with  Polychrome  Methylene-blue.  Goldhorn's 
solution  of  methylene-blue  and  lithium  carbonate  affords  a 
rapidly  acting  stain,  superior  to  all  others  for  the  demon- 
stration of  the  finer  structure  of  the  malarial  parasite  in  every 
phase  of  its  development.  In  addition  to  giving  crisp,  clear-cut 
pictures  of  the  chromatin  of  this  organism,  the  solution  also 
brings  out  distinctly  the  granular  degeneration  of  the  erythro- 
cytes, the  nuclear  characteristics  of  the  erythroblasts  and  leuco- 
cytes, the  basophile  granules,  and  all  ordinary  bacteria. 

Technique  of  Staining.  The  films  are  fixed  for  fifteen  seconds 
in  methyl  alcohol,  rinsed  in  water,  and  then  stained,  unheated, 
for  from  one  to  two  minutes,  after  which  they  are  thoroughly 

1  This  solution  is  made  by  first  adding  4  grms.  of  hematoxylin  crystals,  dissolved 
in  25  cc.  of  alcohol,  to  400  cc.  of  a  saturated  aqueous  solution  of  ammonia-alum. 
The  mixture  is  left  exposed  to  the  sunlight  and  air  in  an  uncorked  bottle  for  four 
days,  at  the  end  of  which  time  it  is  filtered,  and  mixed  with  100  cc.  each  of  methyl 
alcohol  and  glycerine.  This  solution  is  allowed  to  stand  until  it  becomes  dark- 
colored,  when  it  is  filtered,  and  placed  in  a  tightly  corked  bottle,  to  "  age"  for  at 
least  two  months  before  it  can  be  used  successfully  for  staining.  Owing  to  the  com- 
plicated manner  in  which  Delafield's  hematoxylin  must  be  prepared,  it  is  usually  pref- 
erable to  purchase  it  ready-made,  from  a  dealer  in  microscopical  supplies,  Griibler's 
make  being  entirely  reliable. 

2  Johns  Hopkins  Hosp.  Bull.,  1899,  vol.  x.,  p.  70. 


70         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

washed  in  running  water,  dried  without  the  use  of  heat,  and 
mounted  in  balsam.  Preliminar)^  staining  for  ten  or  fifteen  sec- 
onds with  a  o.  I  per  cent,  aqueous  solution  of  eosin,  followed  by 
washing,  gives  a  picture  in  which  the  contrast  between  the  plasma 
and  the  basic  elements  of  the  cells  is  clearly  differentiated.  Poly- 
chrome methylene-blue,  prepared  according  to  Goldhorn's  for- 
mula,^ is  sold  by  dealers  in  laborator}-  supplies,  or  it  may  be 
made  in  this  manner  : — 

Two  grammes  of  methylene-blue  are  dissolved  in  300  cubic 
centimeters  of  warm  water  and  4  grammes  of  lithium  carbonate 
are  added,  with  constant  agitation.  The  mixture  is  poured  into 
an  uncovered  porcelain  capsule,  which  is  heated  over  a  shallow 
water-bath  for  ten  or  fifteen  minutes,  being  frequently  stirred  with 
a  glass  rod.  After  removal  from  the  water-bath,  the  fluid  is  bot- 
tled, without  filtering,  and  set  aside  for  several  days,  after  which 
its  reaction  is  corrected  by  the  cautious  addition  of  a  5  per  cent, 
acetic  acid  solution  until  the  dye  is  but  ver}-  faintly  alkaline. 
Should  the  solution  become  too  alkaline  after  having  been  kept 
for  some  time,  its  reaction  may  be  corrected  by  adding  a  small 
quantity  of  acetic  acid,  as  in  the  preparation  of  the  original 
mixture. 

A  differential  count  of  the  leucocytes  consists  in 
Differential  determining,  by  microscopical  examination  of  the 
Counting,     stained  specimen,  the  relative  percentages  of  the 
different  varieties  of  these  cells,  the  estimate  be- 
ing based  upon  a  count  of  several  hundred  cells,  which  are  clas- 
sified according  to   the  several  forms  described  in   a  following 
section.     (Section    IV.)     This    procedure,   by    means  of  which 
qualitative  changes  affecting  the  leucocytes  may  be  detected,  is 
obviously  a  most  important  step  in  ever)^  blood  examination,  and 
one  which  should  not  be  regarded  as  of  secondary-  importance  to 
the  numerical  estimate  with  the  hemocytometer. 

The  technique  of  differential  counting  consists  simply  in  exam- 
ining successive  microscopical  fields  until  at  least  five  hundred 
leucocytes  have  been  counted,  the  cells  in  each  field  of  \ision 
being  identified  as  they  appear,  and  jotted  down  on  a  piece  of 
paper  by  the  obser\'er  under  their  appropriate  class.  As  soon  as 
the  requisite  number  of  cells  has  been  counted,  the  percentages 
of  the  different  forms  are  calculated,  to  express  the  final  result. 
For  the  examination  a  one-twelfth  inch  oil-immersion  objective  is 
practically  indispensable,  for  to  any  but  the  skilled  worker  it  is 
difficult,  if  not  sometimes   impossible,  to   distinguish  the  various 

^  Johns  Hopkins  Hosp.  Bull.,  1S99,  vol.  x. ,  p.  70.  Also,  X.  Y.  Univ.  Bull,  of 
Med.  Sc. ,  1 901,  vol.  i.,  p.  57. 


COUNTING    THE    BLOOD    PLAQUES.  /I 

forms  of  leucocytes  with  a  lower  magnification  than  this  lens 
provides.  In  order  to  be  certain  that  each  field  is  taken  in  ac- 
curate succession  to  its  neighbor,  the  slide  should  be  moved 
across  the  visual  field  by  the  aid  of  a  mechanical  stage  ;  systematic 
examination  of  any  given  area  of  the  specimen  is  well  nigh  an 
impossibility,  if  the  slide  is  simply  laid  on,  or  clipped  to,  the  stage 
of  the  microscope,  and  pushed  across  it  with  the  fingers  alone. 

If  nucleated  erythrocytes  are  found  in  the  specimen,  it  is 
equally  important  to  include  them  also  in  the  differential  count, 
classifying  them  in  two  histological  divisions,  normoblasts  and 
megaloblasts.  In  calculating  the  number  of  these  cells,  it  is 
obviously  impossible  to  employ  any  direct  method,  so  that  the 
estimate  must  of  necessity  be  more  or  less  approximate,  since  it 
is  based  upon  the  ratio  of  erythroblasts  to  a  given  number  of 
leucocytes.  Having  first  counted  the  latter  with  the  hemocytom- 
eter,  the  number  of  nucleated  erythrocytes  is  noted  in  an  area 
of  the  stained  specimen  in  which  a  fixed  number  of  leucocytes 
is  contained,  and  having  ascertained  these  data,  the  estimate  is 
made  according  to  the  formula  : 

Number  of  erythroblasts  Number  of  leucocytes     •  Nmnber  of 

counted  in  the  stai7ied film         per  cb.  mm.  erythro- 

Number  of  leucocytes  blasts    per 

counted  in  the  stained  film  cb.  mm. 

For  example,  in  a  case  of  pernicious  anemia  in  which  the  leu- 
cocytes number  4,000  per  cubic  millimeter,  and  a  total  of  35 
erythroblasts  are  noted  while  counting  1,000  leucocytes  in  the 
stained  film,  the  calculation  is  as  follows  : 

35  X  4,000  -7-  1,000  =140  erythroblasts  per  cb.  mm. 

Whenever  erythroblasts  are  found,  it  is  important  to  determine 
their  number  to  the  cubic  millimeter  of  blood,  and  should  nor- 
moblasts and  megaloblasts  both  occur,  to  estimate  the  ratio  be- 
tween these  two  types  of  cells. 


V.     COUNTING   THE   BLOOD-PLAQUES. 

Determann's  method^  of  indirectly  estimating  the  number  of 
plaques  to  the  cubic  millimeter  of  blood  is  both  simple  and  ac- 
curate. It  consists,  briefly,  in  first  determining  the  ratio  of  these 
elements  to  the  erythrocytes,  which  are  then  counted,  to  furnish 
the  basis  for  the  final  calculation. 

1  Deut.  Archiv.  f.  klin.  Med.,  1899,  vol.  Ixi.,  p.  365. 


72         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

In  obtaining  the  blood,  a  drop  of  the  diluting  fluid  is  placed 
upon  the  patient's  finger  and  the  puncture  made  through  it,  in 
order  that  the  blood,  as  it  flows  from  the  puncture,  will  instantly 
mix  with  the  diluent  without  coming  in  contact  with  the  air. 
The  blood  and  diluent  are  then  thoroughly  mixed  for  a  few  mo- 
ments by  the  aid  of  a  cover-glass,  after  which  a  small  portion  of 
the  mixture  is  transferred  to  a  Thoma-Zeiss  counting  chamber, 
and  the  ratio  of  plaques  to  erythrocytes  determined  under  the 
microscope.  In  the  healthy  adult  this  ratio,  according  to  Deter- 
mann,  ranges  from  i  to  i8  to  i  to  30,  averaging  about  i  to  22. 
With  another  drop  of  blood  the  erythrocyte  count  is  then  made 
by  the  usual  method,  and  the  actual  number  of  plaques  to  the 
cubic  millimeter  of  undiluted  blood  calculated  from  the  figure 
thus  obtained.  For  example,  in  a  given  specimen  of  blood  in 
which  the  ratio  of  plaques  to  erythrocytes  is  found  to  be  i  to  25, 
the  count  of  the  latter  cells  being  5,000,000,  the  actual  number 
of  plaques  is  therefore  200,000  per  cubic  millimeter. 

The  diluents  for  which  Determann  expresses  a  preference  are 
either  a  9  per  cent,  aqueous  solution  of  sodium  chloride  to  which 
a  little  methyl-violet  has  been  added,  or  an  aqueous  solution  con- 
taining one  per  cent,  of  sodium  chloride  and  5  per  cent,  of 
potassium  bichromate  ;  but  any  of  the  diluting  fluids  already 
mentioned  are  suitable  for  the  purpose. 


VI.    ESTIMATION   OF   THE   RELATIVE   VOLUMES   OF 
CORPUSCLES   AND   PLASMA. 

The  use  of  centrifugal  force  for  the  purpose  of  determining  the 
relative  volumes  of  blood  corpuscles  and  plasma  was  first  applied 
in  a  practical  manner  by  Hedin,^  who  embodied  the  earlier  ideas 
of  Blix  in  an  instrument  known  as  the  hematocrit.  More  re- 
cently Daland,^  by  improving  the  mechanical  construction  of  the 
original  instrument  and  by  simplifying  the  technique  of  using  it, 
has  made  centrifugalization  of  the  blood  a  method  of  investigation 
adapted  to  general  clinical  work.  By  the  use  of  the  hematocrit 
a  pair  of  capillar\'  glass  tubes  filled  with  undiluted  blood  are  ro- 
tated in  their  horizontal  axes  at  a  high  rate  of  speed  until,  as  the 
result  of  the  centrifugal  force  thus  applied,  the  corpuscular. and 
liquid  portions  of  the  blood  become  separated,  the  former  being 
distinguishable  in  the  lumen  of  the  tube  as  a  column  the  length 

1  Skandinavisch.  Arch.  f.   Physiol.,  1890,  vol.  ii.,  p.  1 34. 

2  University  Med.  Magazine,  1891,  vol.  iv.,  p.  85.  Also,  Edwards'  supplement 
to  Keating's  "  Cyclopedia  of  the  Diseases  of  Children,"  Philadelphia,  1899  ;  vol.  v., 
P-  537- 


ESTIMATION    OF    CORPUSCLES    AND    PLASMA. 


73 


Fig.  27. 


of  which  is  dependent  upon  the  volume  which  the  corpuscles  con- 
stitute in  relation  to  the  rest  of  the  blood  mass. 

This  instrument  (Fig.    27)    is    composed  of  a 

Daland's  set  of  cog-wheels  enclosed  in  a  metal  box  and 
Hematocrit,  geared  in  such  a  manner  as  to  cause  ten  thou- 
sand revolutions  per  minute  of  a  vertical  spindle, 
by  turning  a  handle  at  a  definite,  uniform  rate  of  speed.  A 
metal  frame,  which  may  be  securely  fastened  to  the  spindle 
by  a  modified  bayonet-lock,  carries  a  pair 
of  capillary  glass  tubes,  each  of  which 
fits  into  two  cup-Hke,  rubber-lined  de- 
pressions, and  is  adjusted  and  held  in 
place  by  a  spring.  Each  tube  measures 
fifty  millimeters  in  length  with  a  lumen 
of  half-a-millimeter,  and  has  engraved 
upon  its  outer  surface  a  scale  represent- 
ing one  hundred  equal  divisions,  the 
glass  immediately  above  the  scale  being 
moulded  so  as  to  form  a  lens-front,  to 
magnify  the  column  of  blood  and  to 
facilitate  the  reading  of  the  divisions. 
A  bit  of  rubber  tubing,  fitted  with  a 
mouth  piece,  is  used  for  filling  the  capil- 
lary tube,  in  the  same  manner  in  which 
the  blood  is  measured  with  the  hemocy- 
tometer.  While  in  use  the  instrument 
is  securely  attached  to  the  projecting 
edge  of  a  table  or  shelf,  by  means  of  a 
clamp  operated  by  a  thumb-screw. 

Method  of  Use.  Having  cleaned  and  punctured  the  pa- 
tient's finger  in  the  usual  manner,  the  beveled  end  of  one  of 
the  capillary  tubes  is  immersed  in  the  drop  of  blood,  which 
is  sucked  up  the  lumen  of  the  tube  until  it  is  exactly  filled. 
The  forefinger,  smeared  with  a  little  vaseline,  is  then  applied 
to  the  beveled  end  of  the  tube,  while  the  rubber  suction  tube 
is  carefully  removed  by  twisting  it  free — not  by  forcibly  pull- 
ing it  off,  since  this  may  accidentally  cause  removal  of  a 
portion  of  the  blood  column,  by  suction.  The  tube  thus 
charged  with  blood  is  at  once  adjusted  to  one  arm  of  the 
frame,  and  the  empty  tube  similarly  fixed  in  the  other  arm,  to 
equalize  the  balance,  this  step  being  completed  as  rapidly 
as  possible,  in  order  to  anticipate  coagulation.  When  the 
tubes  have  been  thus  adjusted,  and  the  frame  securely  locked  in 
the  spindle,  the  handle  of  the  instrument  is  turned  for  three  min- 


Daland's  hematocrit. 


74         EXAMINATION    OF    THE    BLOOD    BV    CLINICAL    METHODS. 

utes^  at  the  rate  of  seventy-seven  revolutions  a  minute,  this  rate  of 
speed  securing  ten  thousand  rotations  per  minute  of  the  frame,  since 
the  latter  revolves  one  hundred  and  thirty  times  with  each  complete 
turn  of  the  handle.  The  centrifugalization  having  been  finished, 
the  charged  tube  is  carefully  removed  from  the  frame,  and  held 
against  a  piece  of  dull  white  paper,  so  that  the  height  of  the 
blood  column  may  be  easily  determined.  In  order  to  make  the 
reading  with  accuracy,  it  is  sometimes  necessary  to  use  a  small 
magnif>ing  glass,  for  the  divisions  on  the  scale  of  the  tube  are 
but  one-half  a  millimeter  apart — a  distance  too  small  to  judge 
easily  with  the  naked  eye.  On  examination,  three  distinct  di- 
visions of  the  lumen  of  the  tube  containing  the  centrifugalized 
blood  may  be  distinguished  :  first,  a  dark-colored  column  con- 
sisting of  erythrocytes,  reaching,  in  normal  blood,  to  a  point  be- 
tween the  divisions  marked  50  and  51  ;  second,  a  thin  layer  of 
leucocytes,  showing,  in  blood  in  which  these  cells  are  not  largely 
increased,  as  an  indistinct,  milky  stratum  overlying  the  erythro- 
cytes ;  and,  third,  a  layer  of  clear  plasma  occupying  the  remainder 
of  the  lumen.  The  normal  volume  of  erythrocytes  being  arbi- 
trarily regarded  as  one  hundred  per  cent.,  to  compute  this  result 
the  figure  of  the  scale  to  which  these  cells  rise  is  multiplied  by 
two.  Unless  the  leucocytes  are  greatly  increased  in  number,  the 
layer  formed  by  these  cells  is  too  delicate  and  too  dully  defined 
to  be  read  with  any  degree  of  accuracy  ;  but  in  cases  of  high 
leucocytosis  and  of  leukemia  it  is  quite  possible  to  estimate  roughly 
the  relative  proportions  of  leucocytes  to  erythrocytes. 

The  capillar}^  tube  which  has  been  filled  with  blood  should  be 
cleaned  as  soon  after  use  as  possible,  water,  followed  by  alcohol 
and  ether,  being  used  for  this  purpose.  A  fine  wire  should  be 
passed  through  its  lumen,  to  dislodge  any  obstruction  which  may 
result  from  drying  of  the  column  of  closely  packed  corpuscles. 

The  hematocrit,  if  its  clinical  application  is  limited  to  the  de- 
termination simply  of  the  relative  volumes  of  the  blood  corpuscles 
and  plasma,  ma\'  be  relied  upon  to  furnish,  on  the  whole,  de- 
pendable information,  the  necessary  errors  attending  its  use 
probably  being  within  two  per  cent.  If  employed  in  the  role  of 
a  hemocytometer,  however,  its  results  must  needs  be  highly  inac- 
curate just  in  those  instances  in  which  exact  methods  of  investiga- 
tion are  all  important.  It  is  true  that  in  normal  blood,  in  which 
the  size  of  the  corpuscles  ranges  within  the  physiological  limits, 
it  is  correct  to  consider  each  percentage  volume  as  representing 

^  In  a  recent  personal  communication  Dr.  Daland  advises  that,  in  order  to  insure 
the  most  accurate  results  with  his  instrument,  the  centrifugalization  be  continued  for 
three,  instead  of  for  two,  minutes,  as  he  formerly  recommended. 


ESTIMATION    OF    THE   SPECIFIC    GRAVITY.  75 

approximately  a  count  of  100,000  erythrocytes  per  cubic  milli- 
meter. In  blood  characterized  by  any  considerable  deformity  in 
the  size  and  shape  of  these  cells,  as  in  high-grade  anemia  or 
in  leukemia,  it  is  perfectly  obvious  that  no  such  correspondence 
between  the  count  and  the  percentage  volume  can  be  expected — 
blood  in  which  microcytosis  is  pronounced  is  certain  to  show  a 
lower  percentage  volume  of  erythrocytes  than  blood  in  which 
megalocytosis  prevails,  or  than  blood  containing  normal-sized 
cells,  although  the  counts  of  all  three  may  be  identical.  Similarly, 
a  given  number  of  lymphocytes  should  indicate  a  lower  percentage 
volume  than  an  equal  number  of  myelocytes,  or  even  polynuclear 
neutrophiles.  On  account  of  these  sources  of  fallacy,  if  for  no 
other  reason,  the  hematocrit  estimate  should  never  be  taken  as  a 
basis  for  calculating  the  count  in  pathological  conditions,  in  Heu 
of  the  more  accurate,  if  more  laborious,  method  of  counting  the 
corpuscles. 

Capps^  considers  that  the  hematocrit  may  be  used  to  advan- 
tage, in  conjunction  with  the  hemocytometer,  in  determining  the 
actual  size  or  volume  of  the  individual  erythrocyte,  and  he  regards 
this  method  as  far  more  reliable  than  the  use  of  the  micrometer, 
since  with  the  latter  only  the  transverse  diameter  of  the  cells,  and 
not  their  depth,  can  be  measured.  The  formula  for  calculating 
this  "volume  index"  has  been  given  elsewhere.     (See  p.  130.) 


VII.     ESTIMATION  OF  THE  SPECIFIC  GRAVITY. 

This  method  of  investigation  is  used  as  an  indirect  means  of 
computing  the  percentage  of  hemoglobin,  owing  to  the  more  or 
less  constant  parallelism  maintained  between  it  and  the  specific 
gravity  of  the  whole  blood.  The  correspondence  between  the  two, 
together  with  the  sources  of  error  inseparable  from  the  test,  has 
been  pointed  out  in  another  section.     (See  page  98.) 

Hammerschlag's     modification^      of      Roy's 
Hammer-       method^  of  determining  the  specific  gravity  of 
schlag's       the  blood  best  serves  the  purpose  of  those  who 
Method.       choose  this  roundabout  means  of  approximating 
the  hemoglobin  percentage.     It  consists  in  first 
making  a  mixture  of  benzol  and  chloroform  of  such  a  specific 
gravity  that  a  small  drop  of  blood  deposited  in  the  liquid  remains 
suspended,  after  which  the  specific  gravity  of  the  mixture  is  de- 
termined with  a  hydrometer,  the  figure  thus  obtained  representing 

^Journ.  Am.  Med.  Assn.,  1900,  vol.  xxxvi.,  p.  464. 

2Zeitschr.  f.  klin.  Med.,  1892,  vol.  xx.,  p.  444. 

3  Cited  by  Devoto  :  Zeitschr.  f.  Heilk.,  1889,  vol.  xi.,  p.  175. 


^6         EXAMINATION    OF    THE    BLOOD     BY    CLINICAL    METHODS. 

the  density  of  the  blood  used  in  the  test.  The  hemoglobin  per- 
centage corresponding  to  this  figure  is  then  selected  from  a  table 
giving  the  various  degrees  of  blood  densities  and  the  percentages 
of  hemoglobin  to  which  they  are  equivalent. 

The  apparatus  required  for  making  the  test  is  neither  elaborate 
nor  expensive,  a  hydrovicter  prov^ided  with  a  scale  graduated  to 
1.070,  a  hydrometer  jar  having  a  wide,  substantial  base,  a  glass 
capillary  tube,  and  a  glass  stirring  rod  being  the  only  instruments 
needed.  In  most  instances  an  ordinary  urinometer  may  be  used 
instead  of  a  special  hydrometer,  since  specific  gravities  in  excess 
of  1060  (the  highest  gradation  on  the  scale  of  most  urinometers) 
are  not  often  encountered.  Either  a  Thoma-Zeiss  leucocytom- 
eter,  or  a  medicine  dropper  the  free  end  of  which  should  be 
heated  in  a  flame  and  bent  into  an  obtuse  angle,  will  serve  as  a 
capillary  pipette. 

Benzol  and  chloroform  are  mixed  together  in  the  hydrometer 
jar  in  such  proportions  that  the  specific  gravity  of  the  liquid  is 
approximately  equal  to  that  of  normal  blood,  1060.  This  mix- 
ture having  been  made  and  its  specific  gravity  taken,  the  point  of 
the  capillar)^  pipette,  charged  with  blood,  is  plunged  beneath  the 
surface  of  the  liquid  and  a  small  bead  of  blood  gently  expelled. 
If  the  blood  drop  rises  to  the  surface  of  the  mixture  a  few  drops 
of  benzol  are  added,  while  if  it  sinks  to  the  bottom  of  the  jar 
chloroform  is  used,  the  addition  of  the  appropriate  reagent  being 
continued  until  the  drop  neither  rises  nor  sinks,  but  remains  sta- 
tionary, suspended  in  the  mixture.  When  this  point  has  been 
determined  the  specific  gravity  of  the  liquid  is  taken  by  means  of 
the  hydrometer,  this  figure  obviously  representing  the  specific 
gravity  of  the  blood  drop  itself.  To  translate  the  specific  gravity 
into  its  hemoglobin  equivalent  the  figure  obtained  by  the  above 
procedure  is  compared  with  one  of  the  tables  given  on  page  100. 
After  each  addition  of  benzol  or  of  chloroform  the  contents  of  the 
jar  must  be  thoroughly  mixed  by  stirring  with  the  glass  rod,  in 
order  to  secure  uniformity  in  the  density  of  the  liquid.  The  latter, 
if  it  is  filtered  free  from  blood  and  preserved  in  a  tightly  stop- 
pered bottle,  may  be  used  again  in  subsequent  tests. 

In  spite  of  the  enthusiasm  evinced  by  certain  authors  for  this 
method  of  ascertaining  hemoglobin  values,  considerable  experi- 
ence with  the  test  has  convinced  the  writer  that  it  is  both  crude 
and  untrustworthy, — it  is  useful,  no  doubt  when  a  hemometer 
cannot  be  obtained,  but  in  no  sense  is  it  an  efficient  substitute  for 
colorimetric  methods.  The  liability  of  the  blood  drop  to  split 
up  into  numerous  fine  particles,  to  adhere  to  the  inside  of  the  jar, 
and  to  become  altered  in  composition  from  the  influence  of  the 


ESTIMATION    OF    THE   ALKALINITY.  77 

reagents,  as  well  as  the  tedious  attempts  which  must  usually  be 
made  to  add  just  the  proper  quantities  of  benzol  and  chloroform 
to  secure  a  mixture  in  which, the  drop  neither  sinks  nor  rises,  are 
a  few  of  the  drawbacks  which  must  make  the  test  unpopular  with 
busy  clinicians. 


VIII.     ESTIMATION  OF  THE  ALKALINITY. 

The  most  available  clinical  method  of  deter- 
Engel's        mining  the  alkaHnity  of  the  blood  is  by  the  use 
Alkalimeter.  of.Engel's  alkalimeter.     (Fig.  28.)     By  means 
of  this  instrument  a  measured  quantity  of  fresh 
blood  is  diluted  with  distilled  water  in  the  proportion  of  one  to 
ten,  and  then  titrated  with  a  -^L-  normal  solution  of  tartaric  acid 
until  the  mixture  reacts  with  lacmoid  paper,  the  total  alkalinity 
being  calculated  from  the  amount  of  the  tartaric  acid  used.     The 
methods  of  alkalinity  estimation  devised  by  Landois  ^  by  Lieb- 
reich,^  by  Haycraft  and  Williamson,^  by  Wright,^  and  by  Kraus,^ 
are  not  well  adapted  to  routine  blood-work,  being  either  too  com- 
plicated and  elaborate  for  such  a  purpose,  or  too  inaccurate. 

The  apparatus  which  Engel  has  devised  consists  of  the  follow- 
ing parts  :  a  dihiting  and  mixing  pipette,  resembling  a  large-sized 
Thoma-Zeiss  er^^throcytometer  ;  a  graduated  burette  by  means  of 
which  the  amount  of  tartaric  acid  solution  used  in  the  test  is  meas- 
ured ;  a  glass  cylinder  in  which  the  titration  is  made  ;  and  a  glass 
stirring  rod.  The  mixing  pipette  is  graduated  in  three  principal 
divisions  marked  0.025,  0.05,  and  5.0  respectively,  the  first  two 
divisions  being  further  scaled  in  tenths  by  fine  horizontal  mark- 
ings ;  otherwise  the  instrument  is  modeled  like  a  blood  counting 
pipette.  The  burette  has  a  capacity  of  five  cubic  centimeters, 
and  is  provided  with  a  scale  indicating  one  hundred  equal  divi- 
sions ;  when  in  use,  it  is  clamped  upright,  by  means  of  a  special  at- 
tachment, to  a  vertical  brass  support  which  screws  into  a  fitting 
in  the  box  containing  the  apparatus. 

Method  of  Use.  The  technique  of  using  the  alkalimeter  is 
simple  and  time  saving  in  comparison  with  that  required  by  other 
well-known  methods  of  alkalinity  testing.  Finger-blood,  ob- 
tained by  a  rather  deep  puncture  so  as  to  afford  a  good-sized  drop, 
is  sucked  up  in  the  pipette  until  it  reaches  the  mark  0.05,  imme- 
diately after  which  distilled  water  is  similarly  drawn  up  the  lumen 

1  Real-Encyclop.,  1885,  vol.  iii.,  p.  161. 

2  Berichte  d.  deutsch.  chem.  Gesellsch.,  1868,  vol.  i.,  p.  48. 
sProc.  of  the  Roy.  Soc,  Edinburgh,  1888,  June  18. 

*  Lancet,  1897,  vol.  ii.,  p.  719. 
^Zeitschr.  f.  Heilk.,  1889,  vol.  x.,  p.  106. 


7S 


EXAMINATION    OF    THE    BLOOD     BY    CLINICAL    METHODS. 


of  the  tube  until  the  mixture  of  blood  and  water  fills  the  bulbous 
expansion  and  reaches  the  mark  5.0,  in  the  constricted  portion 
beyond.  While  sucking  up  the  water,  the  pipette  should  be  rap- 
idly twisted  to  and  fro  between  the  thumb  and  forefinger,  to  insure 


Fig.  28. 


Engel's  alkalimeter. 

thorough  mixing  of  the  blood  and  water  as  they  together  fill  the 
expanded  portion  of  the  instrument.  As  soon  as  the  dilution  has 
been  made,  the  pipette  should  be  shaken  for  a  minute  or  so,  until 
the  mixture  becomes  of  an  uniform  "laky"  tint,  which  indicates 
that  all  the  hemoglobin  has  been  dissolved  from  the  corpuscular 
stroma.  The  contents  of  the  pipette  are  blown  out  into  the  glass 
cylinder,  which  is  placed  beneath  the  faucet  of  the  burette,  the 
latter  having  been  previously  filled  to  the  mark  o  with  a  y^^^  nor- 
mal solution  of  tartaric  acid.  By  turning  the  stop-cock  of  the 
burette,  the  test  solution  is  now  added,  drop  by  drop,  stirring  be- 
tween each  addition,  to  the  measured  amount  of  diluted  blood 
in  the  cylinder.  From  time  to  time  a  drop  of  the  mixture  is  re- 
moved by  means  of  the  glass  rod  and  tested  with  the  lacmoid 
paper,  the  titration  being  continued  until  the  reaction,  recognized 
as  a  bright  red  halo  which  forms  around  the  edge  of  the  drop,  is 


DETERMINATION    OF    RAPIDITY    OF    COAGULATION. 


79 


obtained.  The  titration  is  then  stopped,  and  a  note  made  of  the 
number  of  drops  of  the  test  solution  which  have  been  used.  In 
normal  blood  the  writer  finds  that  from  9  to  1 1  drops  are  re- 
quired to  give  the  reaction.  The  estimate  of  the  total  alkaHn- 
ity  of  the  blood  is  made  by  multiplying  by  the  figure  53.3,  the 
number  of  drops  of  the  tartaric  acid  solution  used,  according  to 
the  formula,  10  :  a  :  :  533.0  :  ;f,  ^  representing  the  drops  of  the 
reagent.^  The  result  thus  obtained  is  expressed  in  milligrammes 
per  hundred  cubic  centimeters  of  blood.  The  following  table  may 
be  useful  for  reference  in  determining  the  various  degrees  of 
alkalinity  : 

If    6  drops  of  the  solution  are  used  the  alkalinity  equals  319  mgrms.   NaOH 


9 
10 
II 
12 

13 

14 


( (       <(              <( 

((       ((              I  ( 

C(           ((               ( 

(<       <(         I 

( (       (<              (< 

I       ((          ( 

( (       <<              ( ( 

373 
436 
479 

533 
586 

639 
692 
746 


After  use  the  pipette  should  be  thoroughly  washed  out  with 
water,  alcohol,  and  ether,  and  then  dried,  in  the  manner  already 
directed  for  cleaning  the  Thoma-Zeiss  instrument. 

While,  up  to  the  present  time,  it  cannot  be  claimed  that  infor- 
mation of  any  real  diagnostic  pertinence  has  been  obtained  from 
the  study  of  the  alkalinity  of  the  blood,  this  procedure  should 
prove  of  value  in  the  systematic  investigation  of  many  cases,  espe- 
cially those  of  high-grade  anemia.  As  elsewhere  mentioned,  the 
degree  of  normal  blood  alkalinity  varies  greatly  according  to  the 
particular  method  by  which  this  figure  is  ascertained,  so  that  it 
follows  that  the  results  obtained  by  means  of  Engel's  apparatus 
cannot  be  compared  with  those  based  upon  different  methods  of 
research. 

IX.     DETERMINATION   OF  THE   RAPIDITY   OF 
COAGULATION. 

This  procedure  is  obviously  more  useful  in  experimental  labora- 
tory work  than  as  a  means  of  clinical  investigation,  yet  in  some 
diseases,  such  as  hemophilia,  it  will  prove  of  real  value,  since  in 

^Assuming  that  0.5  cc.  of  tartaric  acid  are  used  to  neutralize  0.05  cc.  of  blood, 
therefore  for  every  loo  cc.  of  blood  1,000  cc,  or  one  liter,  of  a  -^-^  normal  solution  of 
tartaric  acid  are  required.  As  the  alkalinity  of  the  blood  is  not  expressed  by  the 
amount  of  acid  necessary  to  saturate  it,  but  in  milligrammes  of  an  alkali,  sodium  hy- 
drate, the  calculation  is  made  thus  :  as  the  equivalent  weight  of  tartaric  acid  is  75, 
and  that  of  sodium  hydrate  40,  one  liter  of  water  dissolving  75  grammes  of  the  for- 
mer saturates  40  grammes  of  the  latter,  that  is,  one  liter  of  a  ^-^  normal  tartaric  acid 
solution  saturates  |§  grammes,  or,  in  other  words,  533  milligrammes,  of  sodium  hy- 
drate, this  figure  being  taken  by  Engel  as  the  degree  of  normal  alkalinity  of  the  blood. 


8o 


EXAMINATION    OF    THE    BLOOD     BY    CLINICAL    METHODS. 


this  condition  it  is  possible  thus  to  determine  the  influence  of 
remedies  administered  with  a  view  to  promoting  coagulation  of 
the  blood.  In  a  number  of  other  pathological  conditions,  char- 
acterized either  by  delay  or  by  unusual  rapidity  of  coagulation, 
this  method  of  research  furnishes  information  which  at  least  adds 
completeness  to  the  clinical  histoiy,  if  nothing  more. 

The  coagulation  time  may  be  determined  ap- 

Glass  Slide  proximately  by  collecting  several  individual  drops 

Method.       of  blood  of  the  same  size  upon  the  surface  of  a 

perfectly  clean,  slightly  warmed  glass  slide.     At 

regular  intervals  of  about  one  minute  a  straw  of  a  whisk-broom  is 

o 

lightly  trailed  through  each  drop  in  succession,  until  sooner  or 
later  a  delicate  thread  of  fibrin  may  be  observed  clinging  to  the 
straw.  The  period  which  has  elapsed  between  the  deposit  of 
the  blood  on  the  slide  and  the  appearance  of  this  indication  of 
clotting  is  expressed  in  minutes,  to  represent  the  coagulation 
time  of  the  specimen  under  investigation.  Normal  blood  thus 
treated  coagulates  in  from  two  and  one-half  to  five  minutes. 

This    instrument    (Fig.    29)   consists   of   a  tin 
Wright's  Co-  water  can  surrounded  by  a  flannel-lined  leather 
AGULOMETER.   jacket  provided  with  nine  pockets,  one  of  which 
is  intended  to  hold  a  thermometer,  and  the  others 
a  set  of  glass  coagulation  tubes.     The  latter  are  each  about  10 
centimeters  in  length,  with  a  lumen  0.25   millimeter  in  diameter, 
and  are  open  at  both  ends  ;  they  should  be  con- 
secutively numbered  or  lettered,  in  order  that  they 
may  be  distinguished  apart  at  a  later  stage  of  the 
test.     The  thermometer  is  of  the  same  outer  di- 
ameter as  that  of  the  tubes,  and  registers  the 
same  degrees  of  temperature  as  an  ordinary-  clin- 
ical thermometer. 

MctJiod  of  Use.  The  central  receptacle  is  first 
filled  with  water  having  a  temperature  of  about 
99°  F.,  and  the  tubes  slipped  into  the  pockets  sur- 
rounding it,  being  allowed  to  remain  in  them  for 
a  few  minutes,  so  that  they  may  become  warmed 
to  the  temperature  of  normal  blood.  Having 
then  pricked  the  patient's  finger,  each  tube  is 
about  half  filled  with  blood,  by  aspiration,  at  suc- 
cessive intervals  of  one  minute,  a  tube  as  soon 
as  it  is  filled  being  replaced  in  its  appropriate 
pocket.  An  equable  temperature  of  the  tubes 
should  be  maintained  by  the  addition  of  hot  water  to  the  can, 
as  its  contents  cool.     Within  three  minutes  after  filling  the  first 


Fig.  29. 


Wright's  coagu- 

LOMETER. 


SPECTROSCOPICAL    EXAMINATION. 


8i 


tube,  it  should  be  tested,  by  blowing  out  its  contents  upon  the 
surface  of  a  sheet  of  white  filter-paper,  the  remaining  tubes  being 
similarly  tested  at  regular  intervals  of  one  minute  or  less,  until 
after  thus  trying  a  variable  number,  one  is  found  from  which  the 
blood  cannot  be  expelled.  Coagulation  may  then  be  con- 
sidered to  have  occurred,  the  time  required  for  this  process 
being  expressed  by  the  number  of  minutes  elapsing  between  the 
filling  of  the  tube  in  question  and  the  evidence  of  clotting  thus 
demonstrated.  With  normal  blood  the  coagulation  time,  as  de- 
termined by  this  instrument,  ranges  from  about  three  to  five 
minutes. 

After  use,  a  fine  wire  should  be  forced  through  the  lumen  of 
the  tubes,  to  dislodge  the  clots,  after  which  the  remaining  traces  of 
blood  are  to  be  removed  by  thorough  washing  with  distilled  water, 
alcohol,  and  ether,  in  the  order  named. 


X.     SPECTROSCOPICAL   EXAMINATION. 

For  clinical  work  the  Sorby-Beck  microspectroscope,  to  be  used 
in  connection  with  the  microscope,  is  an  excellent  instrument, 
being  both  accurate,  and,  comparatively  speaking,  easy  to  manip- 
ulate. Other  very  perfect  instruments  for  the  spectroscopical 
examination  of  the  blood,   differing  but  * 

little  from  the  original  Sorby  model,  are  Fig.  30. 

also  made  by  Zeiss,   by  Leitz,  and  by 
Browning. 

This  instrument  (Fig. 

The  30)  when  in  use  fits  into 

Sorby-Beck    the  tube   of  the  micro- 

MiCROSPECTRO-  scope,  like  an   ordinary 

which    it    is 

Its  essen- 

A,  in  which 


SCOPE. 


ocular,  for 

substituted. 
tial  part  consists  of  a  tube, 
a  series  of  five  prisms,  two  of  flint  and 
three  of  crown  glass,  is  arranged  in  such 
a  manner  that  the  emergent  rays,  which 
are  separated  by  dispersion,  leave  the 
prisms  in  practically  the  same  direction 
as  that  taken    by  the  entering   immer- 

gent  ray.  At  one  side  of  the  tube  is  fixed  a  right-angle  reflecting 
prism,  so  that  the  spectrum  of  a  solution  of  normal  blood  may  be 
thrown  alongside  that  of  the  specimen  under  investigation,  the 
two  spectra  thus  being  comparable.  The  adjustment  of  the 
spectra  is  effected  by  means  of  the  two  small  screws,  B,  B' .  The 
6 


Sorby-Beck  microspectroscope. 


82         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

receptacle  containing  the  control  solution  of  blood  is  clamped  to 
the  stage,  C,  by  a  spring  clip,  D,  light  being  reflected  through 
the  liquid  and  into  the  rectangular  aperture,  £,  by  the  swinging 
mirror,  F.  The  width  of  this  aperture  is  controlled  by  the 
screw,  G.  The  receptacle  containing  the  blood  solution  to  be 
examined  is  placed  upon  the  stage  of  the  microscope,  being 
brought  into  focus  with  a  low-power  (2,^  or  i  inch)  dr>^  objective. 
Beneath  the  tube  enclosing  the  series  of  prisms  is  mounted  an 
achromatic  ocular,  below  which  a  narrow  slit-like  diaphragm  is 
situated,  the  vertical  size  of  this  opening  being  regulated  by  a 
milled  screw,  not  shown  in  the  illustration,  and  its  breadth  by  the 
two  small  levers,  /,  /'.  Both  ocular  and  prisms  may  be  moved 
simultaneously    toward    and    away  from    the    diaphragm,   by   a 

rack-and-pinion    mechanism    controlled    by  the 
Fig.  31.  wheel,  /,  so  that  any  part  of  the  spectrum  may 

be  brought  into  focus. 

The  liquids  to  be  examined  should  be  placed 

in  Sorby's  tubular  cells,  and  cover-glasses  super- 
SORBVT.-BULAR  CELL,  iinposed.     Thcse    cells    (Fig.   31)    are    narrow- 

lumened  glass  receptacles  made  of  barometer 
tubing,  both  ends  of  which  are  accurately  ground  to  parallel 
surfaces,  one  end  being  cemented  to  a  small  polished  glass 
plate. 

Method  of  Examination.  The  specimen  of  blood  obtained  in 
the  usual  manner,  by  puncture,  is  first  diluted  with  distilled  water 
one  hundred  times,  by  means  of  the  Thoma-Zeiss  erjthrocy- 
tometer,  and  sufficient  of  this  laked  blood  dropped  into  a  Sorby 
cell  to  fill  it  exactly  to  the  brim.  A  cover-glass  is  then  carefully 
laid  over  the  open  end  of  the  cell,  the  precaution  being  taken  to 
prevent  the  formation  of  air-bubbles  upon  the  surface  of  the 
column  of  liquid  thus  enclosed.  A  second  cell,  to  be  used  as 
the  control,  is  filled  with  normal  blood,  similarly  diluted,  and 
both  are  then  adjusted  in  their  respective  positions,  as  already 
explained. 

In  making  the  examination,  a  ray  of  artificial  light  (that  from 
a  Welsbach  incandescent  burner  being  most  suitable)  is  projected 
by  the  microscope  mirror  through  the  lumen  of  the  cell  contain- 
ing the  suspected  blood,  and  the  surface  of  the  liquid  focused 
with  an  ordinary  ocular.  The  latter  is  then  removed  from  the 
microscope  tube  and  replaced  by  the  spectroscope  ocular,  and 
the  second  spectrum,  that  of  the  normal  blood,  is  brought  into 
proper  position  alongside  that  of  the  first,  so  that  any  differences 
between  the  two  may  be  contrasted  by  the  observer. 

The  appearance  of  the  spectra  of  normal  and  of  pathological 


BACTERIOLOGICAL  EXAMINATION.  83 

blood,  together  with  the  circumstances  under  which  the  latter 
occur,  have  been  described  in  another  section.     (See  page  123.) 

XI.     BACTERIOLOGICAL    EXAMINATION. 

The  demonstration  of  bacteria  in  the  circulating  blood,  pro- 
vided that  faultless  technique  is  employed,  furnishes  in  some 
instances  a  diagnostic  sign  of  the  greatest  importance.  The 
pathological  significance  of  such  a  finding  is  much  greater  than 
that  of  a  similar  result  obtained  post-mortem,  since  with  the 
latter  there  is  no  means  of  determining  whether  the  bacterial 
invasion  of  the  blood  current  took  place  during  the  active  stages 
of  the  disease,  or  whether  it  occurred  either  as  a  pre-  or  a 
postagonal  process. 

Cultural  methods  with  blood  aspirated  directly 

Methods,  from  a  superficial  vein  should  invariably  be  used 
whenever  such  a  procedure  is  practicable,  for 
blood  obtained  simply  by  pricking  the  skin  is  most  likely  to  be 
contaminated  with  various  bacteria  which  have  their  normal  hab- 
itat in  the  epidermis  and  its  appendages,  notably  by  the  staphyl- 
ococcus epidermidis  albus.  Welch,^  who  first  drew  attention  to 
this  source  of  error,  emphasizes  the  fact  that  no  diagnostic  sig- 
nificance should  be  attached  to  the  demonstration  of  this  bac- 
terium in  blood  obtained  by  puncture  of  the  skin. 

Direct  examination  of  stained  cover-glass  specimens  prepared 
from  finger  blood  gives  either  negative  or  erroneous  results  in  the 
great  majority  of  instances.  In  certain  overwhelming  infections, 
notably  in  some  of  the  severer  forms  of  bubonic  plague,  it  may 
often  be  possible  to  detect  the  specific  micro-organism  in  the 
stained  film,  but  the  method  must  be  regarded  as  too  crude  and 
unreliable  to  furnish  accurate  findings,  in  the  average  case. 

Blood  Cidtures.  In  order  to  secure  the  most  reliable  informa- 
tion from  blood  culturing,  the  systematic  observance  of  three  pre- 
cautions is  essential.  First,  contamination  by  the  skin  bacteria 
above  referred  to  must  be  carefully  avoided,  by  the  thorough  ster- 
ilization of  the  patient's  skin  at  and  adjacent  to  the  site  from  which 
the  blood  is  aspirated.  Second,  not  less  than  0.5  cubic  centimeter 
of  blood  should  be  used  for  each  culture,  since  only  in  rare  in- 
stances are  bacteria  so  numerous  in  the  peripheral  circulation  as 
to  be  demonstrable  in  a  single  drop  of  blood.  Third,  fluid,  rather 
than  solid,  culture  media  should  be  used,  in  sufficiently  large 
quantities  to  dilute  the  blood  freely — about  one  hundred  parts  of 
media  to  each  part  of  blood — the  object  of  this  precaution  being 

^Dennis'  System  of  Surgery,  Phila.,  1895,  vol.  i.,  p.  251. 


84         EXAMINATION    OF    THE    BLOOD    BV    CLINICAL    METHODS. 

to  secure  attenuation  of  the  bactericidal  properties  of  the  blood, 
which  otherwise  might  prove  strong  enough  to  prevent  all  bac- 
terial development. 

For  aspirating  the  blood  the  author  prefers  to  use  the  needle- 
capped  glass  tube  devised  for  this  purpose  by  James  and  Tuttle.' 
(Fig.  32.)  This  consists  of  a  piece  of  glass  tubing  five  inches  in 
length  and  one-quarter  of  an  inch  in  diameter,  having  a  capacity 
oi  about  two  cubic  centimeters  ;  it  is  tapered  at  one  end  and 
ground  to  fit  the  cap  of  a  number  42  hypodermic  needle,  while 
the  free  end  of  the  tube  is  plugged  with  a  bit  of  cotton.  The  ap- 
paratus is  enclosed  in  a  larger  glass  tube  both  open  ends  of  which 
are  also  plugged  with  cotton,  and  sterilized  by  dr}^  heat,  the  aspi- 
rating tube  being  removed  at  the  time  the  blood  is  to  be  collected. 
This  instrument  is  far  superior  to  an  antitoxin  or  a  hypodermic 
syringe  for  the  purpose  intended,  being  simple,  inexpensive,  easily 

Fig.  32. 


Needle  and  tube  for  aspirating  blood  for  culturing. 

sterilized,  and  readily  cleaned  after  use.  It  is  especially  well 
adapted  for  making  cultures  at  a  distance  from  a  laboratory,  where 
the  sterilization  of  an  ordinary  piston-syringe  is  difficult,  if  not 
impossible. 

At  least  six  hours  before  the  aspiration  of  the  blood,  the  skin 
of  the  patient's  arm  at  and  for  some  distance  on  all  sides  of  the 
bend  of  the  elbow  should  be  thoroughly  scrubbed  for  several 
minutes  with  either  a  strong  ethereal  soap  or  with  tincture  of 
green  soap,  after  which  the  part  is  well  rinsed  with  hot  sterile 
water,  and  finally  washed  with  alcohol  and  ether.  A  moist  i  : 
500  bichloride  compress  is  then  applied  over  the  site  thus  cleaned, 
being  'left  in  place  until  the  time  of  the  withdrawal  of  the  blood. 
As  a  preliminary  to  this  operation,  the  dressing  is  removed,  and 
the  part  freely  douched  and  scrubbed  with  hot  sterile  water,  in 
order  to  remove  eveiy  trace  of  the  bichloride.  A  rubber  drain- 
age tube,  previously  sterilized,  is  twisted  tightly  around  the  pa- 
tient's arm  above  the  bend  of  the  elbow  so  as  to  cause  disten- 
tion of  the  superficial  veins  in  this  situation,  and  the  point  of  the 
needle  is  then  thrust  obliquely  into   the  most  prominent  of  these 

^Med.  and  Surg.  Reports  of  the  Presbyterian  Hosp.,  N.  Y.,  1898,  vol.  iii., 
p.  46. 


BACTERIOLOGICAL    EXAMINATION.  85 

vessels,  with  the  result  that  the  blood  immediately  begins  to  flow 
into  the  bore  of  the  instrument.  If,  for  any  reason,  the  force  of 
the  blood  flow  should  fail  to  fill  the  caliber  of  the  tube,  sufficient 
blood  may  be  easily  obtained  by  making  gentle  suction  through 
a  bit  of  rubber  tubing  slipped  over  the  cotton-plugged  end  of  the 
instrument.  While  introducing  the  needle  it  should  be  held 
almost  parallel  to  the  long  axis  of  the  vein,  for  should  it  be 
simply  plunged  into  the  vessel  at  right  angles,  there  is  danger 
that  the  point  will  pass  completely  through  the  vessel  from  wall 
to  wall  and  penetrate  the  surrounding  tissues — an  accident  which 
may  explain  the  cause  of  many  a  "  dry-tap."  The  site  of  the  as- 
piration may  be  made  anesthetic  by  preliminary  freezing  with 
a  spray  of  ethyl  chloride,  but  to  most  patients  the  operation  is  not 
painful  enough  to  necessitate  such  a  procedure. 

Having  thus  collected,  say,  two  cubic  centimeters  of  blood,  the 
contents  of  the  tube  are  divided  equally  among  four  Pasteur  flasks 
each  containing  at  least  fifty  cubic  centimeters  of  broth  or  other 
suitable  fluid  culture  media.  The  flasks  are  then  shaken  for  a 
few  moments,  in  order  to  mix  the  blood  and  media  and  to  dilute 
thoroughly  the  former,  after  which  they  are  placed  in  an  incu- 
bator. The  identity  of  the  growths,  should  any  occur,  remains 
to  be  determined  by  secondary  culturing  and  microscopical  ex- 
amination, for  descriptions  of  which  the  student  should  consult 
text-books  on  bacteriology.  Cultures  made  by  this  technique, 
suggested  by  Adami,^  are  much  more  favorable  to  the  growth 
of  any  bacteria  which  may  be  in  the  blood-stream  than  the  older 
methods  of  using  solid  media. 

Staining  Methods.  In  the  limited  number  of  instances  to  which 
such  methods  are  applicable  the  technique  described  below  will  be 
found  useful. 

An  attempt  should  be  made  to  sterilize  the  skin  of  the  finger 
from  which  the  blood  is  obtained,  by  thoroughly  scrubbing  the 
part  first  with  ethereal  or  green  soap,  and  then  with  a  1:500 
bichloride  solution,  alcohol  and  ether,  in  the  order  named,  this 
being  followed  by  sponging  with  sterile  water.  A  deep  punc- 
ture having  been  made  with  a  needle  which  has  been  sterilized 
by  the  naked  flame,  and  the  first  few  drops  of  blood  escaping 
from  the  wound  allowed  to  drip  away,  one  of  the  succeeding 
drops  is  transferred  by  means  of  a  sterile  platinum  needle  to  the 
surface  of  a  cover-glass  upon  which  a  second  cover-glass  is 
at  once  laid,  the  two  being  drawn  apart,  in  order  to  secure  a 
pair  of  spreads.  The  latter  are  immediately  dried  by  gentle  heat 
and  then  passed  several  times  through   a  Bunsen  flame.     It  is 

^Journ.  Am.  Med.  Assn.,  1899,  vol.  xxxiii.,  p.  15 14. 


86         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

needless  to  add  that  the  cover-glasses  used  for  making  the  films 
must  be  sterilized  by  heat,  and  handled  by  means  of  a  pair  of 
sterile  forceps.  Films  thus  prepared  may  be  stained  with  any  of 
the  basic  aniline  dyes  (thionin,  methylene-blue,  and  methyl-  or 
o-entian-violet  being  most  useful  for  this  purpose),  after  which 
they  are  washed  in  water,  dried,  and  mounted  in  Canada  balsam 
or  in  cedar-oil.  Should  a  double  stained  specimen  be  desired, 
one  of  the  eosin  and  methylene-blue  solutions  referred  to  previously 
may  be  depended  upon  to  give  satisfactory  results. 

Giinther's  method^  will  be  found  useful,  if  the  object  is  to  de- 
stroy the  color  of  the  erj^throcytes,  so  as  to  leave  a  freer  field  of 
vision  for  any  bacteria  which  may  be  present  in  the  film.  Ac- 
cording to  this  method,  the  specimen  is  first  immersed  for  ten 
seconds  in  a  five  per  cent,  aqueous  solution  of  acetic  acid,  until 
the  tint  of  the  hemoglobin  has  entirely  faded  away,  after  which 
the  reagent  is  removed  by  briskly  blowing  upon  the  surface  of 
the  cover-glass  ;  the  latter  is  then  held,  face  downward,  over  the 
open  mouth  of  a  bottle  containing  strong  ammonia  water,  so  as 
to  neutralize  all  remaining  traces  of  the  acid.  The  film  is  now 
stained  for  twenty-four  hours  with  the  Ehrlich-Weigert  fluid 
(contained  in  a  covered  staining  dish),  at  the  end  of  which  time 
it  will  be  found  to  be  colored  a  deep  blue.  It  is  then  decolorized 
by  a  few  seconds'  immersion  in  a  1:14  aqueous  solution  of  nitric 
acid,  until  the  color  fades  to  a  light  green  ;  rinsed  in  alcohol ; 
dried  in  air ;  and  mounted  in  balsam. 

The  Ehrlich-Weigert  fluid  is  prepared  by  adding  from  10  to 
15  drops  of  aniline  oil  to  6  cubic  centimeters  of  distilled 
water,  held  in  a  test-tube.  The  fluid  is  thoroughly  mixed  by 
shaking,  and  then  filtered.  To  the  filtrate  a  few  drops  of  a  con- 
centrated alcohoHc  solution  of  methyl-  or  gentian-violet  is  added 
— just  sufficient  of  the  dye  to  produce  a  slight  turbidity  of  the 
liquid,  which  clears  up  in  a  few  minutes.  The  mixture  prepared 
in  this  manner  is  employed  as  the  staining  agent. 

XIL     DETERMINATION  OF  THE  SERUM  REACTION. 

In    1894  Pfeiffer^  noticed  that  the  vibrios  of 

Widal's        Asiatic  cholera,  if  injected  into   the    peritoneal 

Test.  cavity  of  a   guinea-pig   immunized   against   this 

disease,  rapidly  lost  their  characteristic  motility, 

and  tended  to  become  granular,  broken  up,  and  dissolved,  while 

iForschr.  d.  Med.,  1S85,  vol.  iii.,  p.  775. 

2Zeitschr.  f.  Hvg.,  1894,  vol.  xviii.,  p.  I.  Ibid.,  1895,  vol.  xix.,  p.  75. 
Also,  Centralbl.  f.  Bakt.  u.  Parasitenk.,  1896,  vol.  xix.,  p.  191.  Also,  Deut.  med. 
Woch.,  1896,  vol.  xxii.,  p.  97. 


DETERMINATION    OF    THE    SERUM    REACTION.  8/ 

in  the  healthy,  non-immune  animal  they  developed  normally  and 
abundantly,  and  failed  to  show  any  such  changes  in  their  mor- 
phology. He  claimed  that  this  reaction,  known  as  **  Pfeiffer's 
phenomenon,"  was  specific,  and  emphasized  its  value  as  a  means 
of  laboratory  differentiation.  Two  years  later  Pfeiffer  and  KoUe  ^ 
found  that  the  same  changes  occurred  in  experiments  with  the 
bacillus  of  Eberth  and  animals  rendered  immune  to  enteric  fever, 
and,  furthermore,  discovered  that  the  test  could  be  conducted  in 
vitro,  by  mixing  in  a  test-tube  typhoid  cultures  and  immune  serum. 
It  is  of  interest  to  note  that  results  somewhat  analogous  to  those  of 
Pfeiffer  had  been  observed  in  1891  by  Metchnikoff,^  and  in  1889 
by  Bordet,^  and  by  Charrin  and  Roger,^  although  none  of  these 
workers  appeared  to  recognize  the  significance  of  their  observations. 

In  1896  Griiber  and  Durham^  applied  the  principles  of  Pfeif- 
fer's phenomenon  to  many  other  motile  as  well  as  non-motile 
bacteria,  deduced  new  facts  regarding  its  utility  as  a  means  of 
differentiating  various  species  of  germs,  improved  the  technique 
of  the  test,  and  made  the  important  announcement  that  aggluti- 
nation and  immobility  of  typhoid  bacillus  cultures  were  pro- 
duced by  the  action  of  blood  serum  from  a  patient  having  re- 
cently recovered  from  an  attack  of  enteric  fever.  It  remained, 
however,  for  Widal,*^  in  1896,  first  to  apply  the  reaction  clinically, 
and  to  announce  that  enteric  fever  could  be  diagnosed  by  noting 
the  clumping  and  immobihzation  of  the  typhoid  bacillus  when 
mixed  in  definite  proportions  with  blood  serum  from  a  patient 
suffering  from  typhoid.  This  reaction,  Widal  insisted,  was  one  of 
infection,  and  was  demonstrable  not  only  during  convalescence, 
but  during  the  incipiency  and  the  height  of  the  disease. 

The  serum  reaction  is  to-day  recognized  as  an  important  sign 
in  the  diagnosis  not  only  of  enteric  fever,  but  also  of  Asiatic 
cholera,  of  Malta  fever,  and  of  relapsing  fever,  while  its  value  still 
remains  less  certainly  established  in  many  other  conditions,  such 
as,  for  example,  leprosy,  tuberculosis,  yellow  fever,  bubonic 
plague,  and  pneumococcus  infections.  The  technique  of  the  test 
and  its  diagnostic  significance  under  various  circumstances,  will 

1  Zeitschr.  f.  Hyg.,  1896,  vol.  xxi.,  p.  203.  Also,  Deut.  med.  Woch.,  1896, 
vol.  xxii.,  p.  735. 

2Annal.  de  I'lnstitut  Pasteur,  1891,  vol.  v.,  p.  473.  Ibid.,  1894,  vol.  viii,, 
p.  714.     Ibid.,  1895,  vol.  ix.,  p.  433. 

^Annal.  de  I'lnstitut  Pasteur,  1895,  vol.  ix.,  p.  462.  Ibid.,  1896,  vol.  x., 
p.  191. 

^  Compt.  rend.  Soc.  Biol.,  1889,  9  s.,  vol.  i.,  p.  667. 

sMiinch.  med.  Woch.,  1896,  vol.  xliii.,  p.  285. 

6 Bull,  med.,  1896,  vol.  x.,  pp.  618  and  766.  Sem.  med.,  1896,  vol.  xvi., 
p.  259.  Ibid,,  1897,  vol.  xvii.,  p.  69.  Lancet,  1896,  vol.  ii.,  p.  1371.  Miinch. 
med.  Woch.,  1897,  vol.  xliv. ,  p.  202. 


88         EXAMINATION    OF    THE    BLOOD    BY    CLINICAL    METHODS. 

be  described  under  the  headings  of  the  diseases  in  which  it  occurs. 
(See   "  General  Hematology.'') 

Originally  Bordet/  more  recently  Uhlenmuth,- 

The  Specific  and  Wassermann    and    Schutze'^    have  demon- 
Test  for       strated  the  important  fact  that  the  blood  serum 

Human  Blood  of  an  animal  subcutaneously  injected  with  the 
blood  of  another  animal  of  a  different  species 
rapidly  develops  the  property  of  agglutinating  and  dissolving  the 
er^^throcytes  similar  to  those  injected,  but  has  no  effect  upon 
blood  derived  from  any  other  source.  The  last-named  ob- 
servers, for  example,  administered  to  rabbits,  at  intervals  of  two 
days,  several  subcutaneous  injections  of  lo  cubic  centimeters 
each  of  defibrinated  human  blood,  the  animals  being  bled  to 
death  six  days  after  the  last  dose,  and  their  shed  blood  placed 
upon  ice,  to  effect  separation  of  the  serum.  Sufficient  blood  for 
this  purpose  may  be  readily  obtained  by  wet-cupping,  leeching, 
or  placental  expression.  If  0.5  cubic  centimeter  of  this  rabbit- 
serum  (or  ''antiserum"  for  human  blood)  is  added  to  a  solution 
of  the  blood  of  man,  diluted  about  one  hundred-fold  with  distilled 
water  or  with  normal  salt  solution,  a  distinct  cloudy  precipitate 
rapidly  occurs  at  ordinary  room  temperature,  the  turbidity  be- 
coming much  more  dense  after  brief  incubation  of  the  mixture  at 
^y^  C.  On  the  contrary,  no  definite  change  occurs  on  the  ad- 
dition of  the  serum  to  the  diluted  blood  of  other  animals,  no 
less  than  twenty-three  different  species  having  failed  uniformly  to 
react  positively,  with  the  single  exception  of  the  monkey,  and  in 
this  instance  the  reaction  was  delayed  and  incomplete,  being  in 
no  way  comparable  to  the  prompt  cloudiness  produced  by  the 
mixture  of  human  blood  with  its  antiserum.  Old  dried,  and  even 
putrefied  blood,  diluted  i  to  100  with  normal  salt  solution,  has  been 
found  to  react  typically,  while  Nuttal  and  Dinkelspiel  ^  have  re- 
ported characteristically  positive  results  with  human  blood  mixed 
with  an  equal  volume  of  the  diluted  blood  of  different  animals, 
such  as  sheep,  oxen,  horses,  and  dogs.  These  workers  also  found 
that  positive  results  were  obtained  with  human  nasal  and  lachr)'mal 
secretions.  Uhlenmuth  ^  discovered  that  blood  specimens  could 
be  frozen  for  two  weeks  at  a  temperature  of  10°  below  zero,  C, 
without  in  any  way  affecting  the  sensitiveness  of  the  reaction, 
and  that  blood  mixed  with  soapy  water,  menstrual  urine,  and 
other  contaminating  liquids  responds  promptly  and  typically. 

^Annal.  de  I'lnstitut  Pasteur,  189S,  vol.  xii.,  p.  688.    Ibid.,  1899,  vol.  xiii.,  p.  273. 
2  Deut.  med.  Woch.,  1901,  vol.  xxvii.,  p.  82. 
3Berl.  klin.  \Voch.,  1901,  vol.  xxxviii.,  p.  187. 
••Brit.  Med.  Journ.,  1901,  vol.  i.,  p.  1141. 
^Loc.  cit. 


DETERMINATION    OF    THE    SERUM    REACTION.  89 

From  a  medico-legal  standpoint,  the  value  of  this  test  is  ob- 
vious, for,  even  at  this  early  stage  of  its  development,  it  has 
received  sufficient  corroboration  to  justify  its  use  as  a  means  of 
identifying  human  blood  stains,  no  matter  how  old  and  how 
contaminated  they  may  be.  For  this  purpose,  the  reaction  ap- 
pears to  be  entitled  to  much  greater  confidence  than  the  spec- 
troscope, or  chemical  tests. 


SECTION    II. 


THE  BLOOD  AS  A  WHOLE. 


SECTION   II. 
THE   BLOOD   AS   A   WHOLE. 


I.    GENERAL  COMPOSITION. 

Blood  is  a  tissue  consisting  of  fluid  and  cor- 
Plasma,  Serum  puscular  elements,  the  former  constituting  about 
AND  Cells,  three-fifths,  and  the  latter  two-fifths  of  its  total 
volume.  It  has  been  approximated  that  the  total 
quantity  of  blood  in  the  normal  individual  is  from  yL  to  -^j  of  the 
body-weight,  the  proportion  being  somewhat  less  in  the  infant 
than  in  the  adult.  The  fluid  element  of  the  blood,  known  as  the 
plasma  or  liquor  sanguinis,  is  an  alkaline,  yellowish  liquid,  of 
a  specific  gravity  ranging  from  about  1026  to  1030,  and  con- 
taining approximately  ten  per  cent,  of  solid  matter,  of  which 
three-fourths  are  proteids ;  the  latter  consist  of  fibrinogen, 
serum-albumin,  and  serum-globuHn.  Coagulation  of  the  blood 
results  in  its  separation  into  a  densely  reticulated,  somewhat 
granular  substance,  fibrin,  and  into  a  clear,  straw-colored,  alka- 
line fluid,  serum.  Fibrin  is  a  sparingly  soluble,  highly  elastic, 
proteid  body,  which  encloses  and  imprisons  within  its  multitude 
of  delicate  fibrils  the  corpuscular  elements,  the  whole  forming  the 
blood-clot  or  crassamentum.  Serum  is  a  clear,  straw-colored,  alka- 
line fluid,  having  a  specific  gravity  of  about  1026  and  containing 
practically  the  same  amount  of  solids  and  relative  proportion  of 
proteids  as  are  found  in  the  plasma ;  its  proteid  constituents  are 
fibrin-ferment,  which  replaces  the  fibrinogen  of  the  plasma,  serum- 
albumin,  and  serum-globulin. 

The  corpuscular  elements  of  the  blood  are  free  cellular  bodies 
suspended  in  the  plasma.  They  are  of  two  varieties  :  the  eryth- 
rocytes or  red  corpuscles,  and  the  leucocytes  or  ivhite  corpuscles. 
In  addition  to  these  cells,  two  other  elements  are  also  found, 
namely,  the  blood-plaques,  and  the  hemoconia,  although  these 
bodies,  while  they  may  be  conveniently  grouped  with  the  red  and 
white  cells,  are  not  to  be  regarded  as  definite  corpuscular  entities. 

The  salts  of  the  blood  include  sodium  chloride,  potassium 
chloride,  sodium  carbonate,  sodium  phosphate,  magnesium  phos- 
phate, calcium  phosphate,  and  sulphates  ;  of  these  salts  sodium 
chloride  is  the  most  abundant,  constituting  from  60  to  90  per 
cent,  of  the  total  amount  of  mineral  matter. 


94  THE    BLOOD    AS    A    WHOLE. 

Certain  extractives  are  also  found,  among  which  are  urea  and 
uric  acid,  creatine,  creatinine,  xanthine,  hypoxanthine,  sugar,  fats, 
soaps,  and  cholesterine. 

The  gases  of  the  blood  consist  of  oxygen,  nitrogen,  and  carbon 
dioxide,  the  former  existing  chiefly  in  combination  with  hem- 
oglobin in  the  er>'throcytes,  and  the  latter  as  carbonates  ;  the 
nitrogen  is  held  in  simple  solution.  About  60  volumes  of  gas  are 
contained  in  each  100  volumes  of  blood.  Arterial  blood  contains 
roughly  20  volumes  of  oxygen,  and  40  of  carbon  dioxide,  while 
venous  blood  contains  less  than  10  volumes  of  oxygen,  and  almost 
50  of  carbon  dioxide  ;  the  quantity"  of  nitrogen  in  both  arterial 
and  venous  blood  is  from  i  to  2  volumes. 

II.    COLOR. 

The  distinctive  color  of  the  blood  is  due  to 
Normal       the  presence  of  the  hemoglobin  contained  in  the 
VARLA.TIONS.     erj'throcytes,  and  alterations  in  the  chemical  com- 
position of  this  pigment  produce  corresponding 
changes  in  the  color  of  these   cells,  and,   consequently,  in   the 
naked-eye  appearance  of  the  whole  blood.     The  color  of  arte- 
rial blood  is  bright  scarlet,  inasmuch  as  it  contains  a  large  amount 
of  oxj^'gen  in  chemical  combination  with  the  hemoglobin  ;  while 
venous  blood,  on  the  other  hand,  is  of  a  dark  purplish-blue  tint, 
owing  to  its  deficiency  in  oxygen  and  to  the  presence  of  more  or 
less  uneliminated  carbon  dioxide.     This  difference  in  color  is  so 
obvious  that  a  cursory  glance  suffices  to  distinguish  arterial  and 
venous  bloods. 

The  presence  of  immense  numbers  of  hemo- 

Density       globin -containing  elements  accounts  for  the  vary- 

AND  ing    degree  of   density   and    opacity  which    the 

Opacity.        blood  possesses,  distinguishing   it   from  a  mere 

transparent,  colored  fluid.     If,  for  any  reason,  the 

hemoglobin  escapes  from  the  erythrocytes  into  the  surrounding 

plasma,  this  characteristic  opacity  is  quickly  lost,  and  the  blood 

becomes  transparent,  and  of  a  "  laky  "  color.     The  density  and 

the  opacity,  and,  consequently,  the  color  of  the  blood  increases  and 

diminishes  according  to  the  fluctuations  which  occur  in  the  relative 

amounts  of  plasma  and  erythrocytes,  and  also  according  to  the  cells' 

richness  in   hemoglobin,  irrespective  of  their  numerical  variation. 

In  anemic  conditions  the  blood  is  usually  pale 

Pathological  in   color,   somewhat   transparent,   and   thin   and 

Variations.     water>^-looking.     This  is  the  case  particularly  in 

primary  peniicioiis  anemia,   in   chlorosis,    and  in 

Iciikeinia  ;  in  the  former  disease,  it  is  sometimes  difficult  to  believe 


REACTION.  95 

that  the  watery,  pale  fluid  which  flows  from  the  puncture  is  any- 
thing but  pure  serum  ;  in  leukemia,  the  blood  drop  may  have  a 
peculiar  light,  mottled,  streaked  appearance,  or  an  uniform  milky- 
white  tint  may  predominate  over  the  normal  red  hue.  In  cases 
of  dyspnea,  arterial  blood,  because  of  its  inadequate  oxygenation, 
may  be  dark  blue,  closely  resembling  blood  from  the  veins.  This 
similarity  has  also  been  noted  in  cases  of  poisoning  by  sulphur- 
etted hydrogen,  in  which  condition  the  blood  may  even  be  changed 
to  a  dark  greenish  tint.  In  some  cases  of  diabetes  mellitus,  the 
presence  of  large  quantities  of  free  fat  in  the  circulation  seem- 
ingly divides  the  blood  drop  into  two  distinct  layers,  an  upper, 
light-colored  portion,  containing  supernatant  fat-droplets,  and  a 
lower,  darker  layer  of  pure  blood ;  at  first  glance  diabetic  blood 
has  a  somewhat  pinkish  hue. 

In  poisoning  by  aniline,  nitrobenzol,  hydrocyanic  acid,  and  potas- 
sium chlorate,  the  blood  is  chocolate-  or  dun-colored ;  and  in 
poisoning  by  carboji  monoxide,  bright  cherry- red.  In  severe 
icterus  a  yellowish-red  tint  of  the  blood  has  been  observed. 

III.    ODOR  AND   VISCOSITY. 

Owing  to  the  presence  of  certain  volatile  fatty  acids,  blood 
possesses  a  peculiar  and  characteristic  odor  or  halitus,  which  may 
be  intensified  by  the  addition  of  concentrated  sulphuric  acid,  and 
which  rapidly  disappears  after  the  withdrawal  of  the  blood  from 
the  body.  The  slippery  feeling  of  freshly  drawn  blood  is  quickly 
lost  after  its  exposure  to  the  atmosphere,  and  is  replaced  by  a 
viscosity  or  stickiness,  as  coagulation  progresses. 

IV.    REACTION. 

Under  normal  conditions,  the  reaction  of  the 
Reaction      blood  is  alkaline,  owing  chiefly  to  the  presence 
IN  Health,     of  sodium  carbonate  and    disodium    phosphate. 
Clinically,  the  degree  of  alkalinity  is  determined 
by  ascertaining  the  amount  of  sodium  hydroxide   which  is  ex- 
actly neutralized  by  one  hundred  cubic  centimeters  of  blood,  the 
result  being  usually  expressed  in  milligrammes  of  NaOH  per 
hundred  cubic  centimeters  of  blood.     The  figures  given  by  differ- 
ent  investigators    as   representing    the   normal   alkaHnity   range 
within  the  widest  limits,  chiefly  in  consequence  of  the  many  dif- 
ferent methods  by  which  such  data  were  obtained.     In  view  of 
these    marked    discrepancies,  the  alkalinity  figures   of  different 
workers  are  in  no  sense  comparable  unless  they  are  based  upon 
precisely  similar  methods  of  investigation  pursued  with  identical 


96 


THE    BLOOD    AS    A    WHOLE. 


technique.  The  following  table,  compiled  from  reliable  data,  il- 
lustrates the  range  of  the  normal  blood  alkalinity,  as  estimated 
by  various  observ^ers  : 

Observer.  Degree  of  Alkalinity. 

Kraus 162-232  mgrms.  NaOH  per  loo  cc.  of  blood. 

Burmin 182-218  "  "  «'  "  "  " 

Rumpff. 182-218  "  "  "  ''  "  " 

Jeffries 200  "  "  "  "  "  " 

Freudberg 200-240  "  "  "  "  "  " 

Lepine 203  «'  "  "  "  "  " 

Canard 203-276  "  "  *'  "  "  " 

Drouin    206  "  "  "  "  "  " 

Von  Limbeck 218  *'  «*  ''  "  "  " 

Zuntz  and  Lehmann 240  "  "  *'  '*  "  " 

Von  Taksch 260-300  ''  *'  "  "  "  '* 

Schuitz-Schultzenstein 260-300  "  "  «'  "  "  " 

Strauss 300-350  "  "  "  "  *'  " 

Brandenburg..... 330-370  "  "  "  "  "  ** 

Lowy 449  "  "  "  "  "  " 

Berend 450-500  "  "  "  "  "  " 

Engel 479-533  "  "  "  "  "  " 

Mya  and  Tassinari 516  *'  *'  "  *'  "  " 

• 

With  the  titration  method,  now  generally  admitted  to  furnish 
fairly  accurate  results,  appreciably  higher  figures  are  obtained 
with  laked  whole  blood  than  with  serum  alone,  since  by  the 
former  method  the  alkalinity  of  all  the  plasma  and  cellular  ele- 
ments is  estimated,  while  by  the  latter  the  influence  of  the  cor- 
puscles is  entirely  eHminated. 

The  alkalinity  of  the  blood  is  slightly  higher, 
Physiological  as  a  general  rule,  in  7He/i  than  in  zvoinen  and 
Variations,  children,  and  is  somewhat  influenced  by  the  time 
of  day,  being  at  its  minimum  during  the  early 
morning  hours,  gradually  rising  during  the  afternoon,  and  falling 
aeain  during;  the  eveninor.  Some  observers  maintain  that  it  is 
increased  during  the  pcj'iod  of  digestion,  but  this  fact  is  dis- 
puted by  others.  It  is  temporarily  diminished  by  the  effects  of 
muscidar  exercise,  and  by  a  diet  deficient  in  yiitrogenotis  substances ; 
on  the  contrary,  richly  nitrogenous  food  eaten  during  the  per- 
formance of  muscular  work  overcomes  the  effect  of  such  exertion 
in  lowering  the  alkalinity.  The  effects  of  cold  baths  are  said  to 
increase  the  alkalinity  of  the  blood. 

In  health,  by  the  perfect  mechanism  of  the  emunctoiy  organs 
of  the  body,  the  normal  balance  of  blood  alkalinity  is  constantly 
maintained,  in  spite  of  the  entrance  of  acids  into  the  blood, 
whether  by  the  ingestion  of  acid  substances,  or  by  their  produc- 
tion within  the  system,  for  the  excess  acidity  from  such  causes 
is  promptly  removed  from  the  blood  by  the  action  of  the  kidneys, 


REACTION.  97 

the  skin,  and  the  lungs.  Thus,  the  ingestion  of  acids  is  quickly 
followed  by  increased  acidity  of  the  urine  and  sweat,  while  at  the 
same  time  an  increased  quantity  of  carbon  dioxide  is  given  off  by 
the  lungs.  It  is  also  probable  that  the  tendency  to  acidity  is 
partly  neutralized  by  the  ammonium  salts  generated  from  proteid 
foods,  and  by  the  action  of  the  liver. 

Increased  alkalinity  goes  hand  in  hand  with  increased  aritidotal 
action  of  the  blood  against  bacterial  infection,  as  experiments  have 
shown  that  animals  whose  blood  had  been  artificially  rendered 
highly  alkaline,  by  the  administration  of  sodium  salts,  showed 
much  greater  resistance  to  the  effects  of  virulent  micro-organisms, 
than  untreated  animals.  Therefore,  it  is  believed  that  the  power 
of  immunity  against  infections  may,  to  a  certain  degree,  be  meas- 
ured by  the  alkalinity  of  the  blood,  for,  in  animal  experimenta- 
tion, the  fact  is  evident  that  the  greatest  degree  of  blood  alka- 
Hnity  is  found  in  animals  whose  immunity  is  absolute. 

Unfortunately,  the  question  of  alteration  in  the 

Tathological  alkalinity  of  the  blood   in  various  pathological 

Variations,     conditions  is  at  the  present  time  one  about  which 

the   opinions  of  different  observers    conflict,  so 

that  conclusions  concerning  this  subject  must  be  accepted  with 

more  or  less  reserve. 

It  is  of  interest,  however,  to  note  that  most  observers  agree 
that,  as  a  rule,  the  alkalinity  of  the  blood  is  perceptibly  lowered  in 
those  diseases  associated  with  2.  febrile  movement,  but  no  definite 
relation  between  the  intensity  of  the  pyrexia  and  the  degree  of 
lessened  alkalinity  has  been  established.  Subnormal  alkalinity 
figures  have  also  been  met  with  in  the/rz;;^<2r;/and  secondary  ane- 
mias, with  the  exception  of  chlorosis,  in  which  condition  the  blood 
alkalinity  usually  is  either  normal,  or  perhaps  slightly  increased. 
Desevres  ^  has  drawn  attention  to  the  fact  that  in  the  early  stages 
of  acute  diseases  the  alkalinity  is  either  normal  or  somewhat  in- 
creased, and  in  the  majority  of  instances  it  becomes  perceptibly 
diminished  during  convalescence.  In  chronic  diseases  it  is  usu- 
ally decreased  if  the  duration  of  the  disease  has  been  of  long 
standing. 

Drouin  ^  found  a  lessened   alkalinity   of  the  blood   in   enteric 
fever,  in  pneumonia,  in  malarial  fever,  in  diphtheria,  in  rheumatic 
fever,  in  erysipelas,  in  appendicitis,  and  in  many  other  acute  infec- 
tions.     Cantani  ^  maintains  that  in  the  algid  stage  of  Asiatic  chol- 
era the  reaction  of  the  blood  during  life  in  some  cases  may  be 

^  These  de  Lyon,  1897-98. 

2  "  Hemo-alcalimetrie  et  Hemo-acidimetrie, "  These  de  Paris,  1892,  n.  83. 

^Centralbl.  f.  d.  med.  Wissensch.,  1884,  vol.  xxii.,  p.  785. 

7 


98  THE    BLOOD    AS    A    WHOLE. 

even  acid,  and  that  the  alkalinity  is  always  markedly  reduced. 
Von  Jaksch/  Peiper,-  Kraus,^  and  others  state  that  the  alkalinity 
is  generally  diminished  in  uremia,  in  diabetes,  in  osteomalacia,  in 
organic  diseases  of  the  liver,  and  in  poisoning  by  caj'bon  mon- 
oxide and  by  phosphorus,  especially  by  the  latter.  Decreased 
alkalinit>^  has  also  been  noted  in  choleinia,  in  Addison' s  disease, 
in  Hodgkin' s  disease,  in  poisoni7ig  by  mineral  acids,  in  the  late 
stages  of  malignant  neoplasms,  and  in  various  long-standing 
cachectic  conditions.  Thomas  ^  found  the  alkalinit)'  reduced  in 
acute  alcoholis?n,  and  as  the  result  of  chloroform  narcosis.  Tchle- 
norff^  found  a  diminished  alkalinity  in  a  wide  variet}"  of  skin 
diseases,  among  which  are  named  psoriasis,  eczenia,  pemphigus, 
purpura  hemorrhagica,  eyythema  midtifoi-me,  lichen  rubra,  and 
elephantiasis.  Since  it  was  also  found  that  the  administration  of 
arsenic  failed  to  increase  the  blood  alkalinity',  the  action  of  this 
drug  upon  dermatoses  is  evidently  not  due  to  its  influence  upon 
the  blood. 

In  organic  diseases  of  the  heart  unassociated  with  pyrexia,  and 
in  nervous  diseases  the  alkalinity  of  the  blood  has  been  found  to 
be  increased.  In  chronic  rheumatism,  and  in  renal  lesions  unac- 
companied by  uremic  symptoms  the  reaction  of  the  blood  is  usu- 
ally found  to  be  unaltered. 


V.     SPECIFIC    GRAVITY. 

In   the   majority   of   healthy   male  adults  the 
Normal       specific  gravity  of  the  blood  varies  from  1055  to 
R.\NGE.         1065,  the  average  being  in  the  neighborhood  of 
1060.     In  ivomen  the  average  is  somewhat  less, 
about  1056;  in  children  it  is  about  105 1,  and  in  neiv-born  i?ifa?its 
1066  is  considered  normal.     Diurnal  variatiojis  in  the  specific 
gravity  have  been  noted,  but  these  fluctuations  are  slight   and 
unimportant.     The  blood  densit)'  of  habitual  dwellers  in  high  alti- 
tudes is  distinctly  increased.      Venous  blood  is  said  to  be  of  slightly 
higher  specific  gravity  than  arterial.     The  average  specific  gravity 
of  the  blood  of  the  two  sexes,  as  determined  by  the  principal  ob- 
servers, is  as  follows  : 

*  Deut.  med.  Woch.,  1893,  vol.  xix.,  p.  10. 
^Archiv.  f.  Pathol.  Anat.,  1889,  vol.  cxvi.,  p.  337. 
3Zeitschr.  f.  Heilk.,  1889,  vol.  x.,  p.  106. 

*  Archiv,  f.  exper.  Pathol,  u.  Pharm.,  1898,  vol.  xli.,  p.  I. 

5  Vratch,    1898,   vol.   xix.,   p.    248.      Abst.,   Joum.    of  Cutan.   and    Genito-Ur. 
Dis.,  1898,  vol.  xvi.,  p.  544. 


SPECIFIC    GRAVITY.  99 


Authority. 

Males. 

Females. 

Askanazy, 

1060. I 

1056.4 

Schmidt, 

1060 

1050 

Hammerschlag, 

1061.5 

1057-5 

Lloyd  Jones, 

105S.5 

1051-5 

Landois, 

1057.5 

1056 

Becker, 

1057 

1056.5 

Schmaltz, 

1057 

1056 

Peiper, 

1055 

1053 

From  a  clinical  standpoint,  the  specific  gravity 
Pathological  of  the  blood  may  be  regarded,  within  certain 
Variations.  Hmits,  as  a  tolerably  accurate  index  to  the 
corpuscular  richness  of  this  tissue,  and  to  the 
hemoglobin  equivalent  of  the  erythrocytes,  since  fluctuations  in 
these  constituents  immediately  give  rise  to  corresponding  altera- 
tions in  the  density  of  the  blood-mass.  It  follows,  then,  that  in 
the  various  conditions  of  anemia,  characterized  by  corpuscular 
and  hemoglobin  losses,  low  specific  gravities  are  encountered  ; 
on  the  other  hand,  it  is  also  obvious  that  in  conditions  of  polycy- 
themia, the  cellular  increase  and  the  high  hemoglobin  equivalent 
are  mirrored  by  the  corresponding  rise  in  the  density  of  the 
blood.  An  increase  promptly  follows  any  sudden  drain  upon 
the  fluids  of  the  system  sufficient  to  cause  inspissation  of  the 
blood,  such  as  may  result  from  copious  diarrhea,  free  sweating, 
or  hyperemesis  ;  while  the  density  is  at  once  lowered  as  the  re- 
sult of  sudden  dilution  of  the  blood,  following,  for  example,  the 
injection  of  a  large  quantity  of  saline  solution,  or  even  the  inges- 
tion of  a  large  volume  of  liquid.  Fluctuations  in  the  specific 
gravity  of  the  blood  under  such  circumstances,  which  are  purely 
physiological  in  character,  are  invariably  of  transient  duration, 
for  the  normal  relation  between  the  relative  volumes  of  corpuscles 
and  plasma  becomes  quickly  reestablished  by  means  of  the  liquid 
interchange  between  the  tissues  and  the  blood-vessels. 

Owing  to  the  fact  that  in  most  instances  a  close  relationship 
exists  between  the  amount  of  hemoglobin  and  the  specific  gravity, 
some  investigators  are  accustomed  to  take  this  parallelism  as  a 
basis  for  calculating  the  percentage  of  hemoglobin  in  the  blood. 
Thus,  by  determining  the  specific  gravity,  and  by  comparing  the 
figure  thus  obtained  with  a  table  giving  the  hemoglobin  equiva- 
lents corresponding  to  varying  degrees  of  blood  density,  fairly  ac- 
curate results  have  been  obtained.  The  following  hemoglobin 
equivalents  of  different  specific  gravities  of  the  blood  have  been 
determined  by  Hammerschlag,^  and  by  Lichty.^ 

^  Loc.  cit. 

2Phila.  Med.  Journ.,  1898,  vol.  ii.,  p.  242. 


100 


THE    BLOOD    AS    A    WHOLE. 


Hammerschlag. 

specific  gravity. 

Hemoglobin  equivalent. 

1033-1035 

25-30 

per 

cent. 

1035-1038 

30-35 

1038-1040 

35-40 

1 040-1 045 

40-45 

1045-1048 

45-55 

1048-1050 

55-65 

1050-1053 

65-70 

1053-1055 

70-75 

1055-1057 

75-85 

1057-1060 

85-95 

ICHTY. 

Hemoglobin  equi 

valetit. 

25-30  per 

cent. 

30-40    '' 

'  • 

40-45    '' 

45-50    '' 

50-55    " 

55-65    '' 

65-70    '' 

70-75    '' 

75-85    '' 

85-95    '' 

95-100  '' 

the  variations  in 

Specific  gravity 
IO35-I038 
1038-1043 
IO43-I045 
I045-I047 
I047-1049 
I049-I052 
I052-1054 
I054-I056 
I056-1060 
1060-1063 
I063-1065 

It  will  be  noted  that  in  both  these  tables  the 
gravit}^  are  somewhat  greater  in  high  than  in  low  hemoglobin 
percentages.  It  has  been  stated  by  Diabella  ^  that,  on  the  aver- 
age, a  difference  of  10  per  cent,  in  hemoglobin  corresponds  to 
4.46  parts  per  thousand  in  specific  gravity  :  and  that  differences 
amounting  to  from  3  to  5  parts  per  thousand  in  the  specific  grav- 
ity may  arise  from  the  influence  of  the  stroma  of  the  erythrocytes, 
in  blood  characterized  by  a  striking  disturbance  in  the  parallelism 
which  normally  exists  between  these  cells  and  the  hemoglobin. 

In  the  clinical  application  of  this  indirect  method  of  computing 
hemoglobin  percentages,  several  conditions,  in  which  factors  other 
than  the  presence  of  hemoglobin  in  the  erj'throcytes  influence  the 
specific  gravity,  must  be  excluded.  In  leukemia,  for  example,  it 
will  be  found  that  hemoglobin  percentages  based  on  the  above 
tables  are  much  higher  than  actually  exist,  the  cause  of  this  fal- 
lacy being  the  presence  of  enormous  numbers  of  leucocytes  in  the 
blood  ;  in  pernicious  anemia  the  hemoglobin  is  frequently  higher 
than  thei  specific  gravity  indicates,  for  in  this  disease  the  individ- 
ual corpuscles  are  much  richer  in  hemoglobin  than  normal ;  and 
in  conditions  associated  with  extensive  dropsy  the  hemoglobin 
percentage  does  not  parallel  the  specific  gravity,  owing  to  the 
abnormally  high  proportion  of  fluids  in  the  blood  mass. 

These  three  sources  of  error,  aside  from  the  rather  tr}'ing  tech- 
nique by  which  one  must  first  determine  the  specific  gravity'  of 
the  blood  drop  (see  page  75),  are  sufficient  to  make  most  work- 
ers reluctant  to  adopt  this  method  as  a  substitute  for  the  hemom- 
eter. 

VI.     FIBRIN   AND    COAGULATION. 

The  essential  factor  of  coagulation  of  the  blood  is  the  forma- 
tion of  fibrin,  a  proteid  substance,  produced  in  the  plasma,  after 

^  Deut.  Archiv.  f.  klin.  Med.,  1S96,  vol.  Ivii.,  p.   302. 


FIBRIN    AND    COAGULATION. 


lOI 


the  withdrawal  of  the  blood  from  the  body,  by  complex  chemical 
changes  occurring  between  the  soluble  calcium  salts  and  the 
nucleo-proteids  of  the  blood,  with  the  consequent  production  of  a 
fibrin  ferment.  The  theories  regarding  coagulation  are  numer- 
ous, conflicting,  and  unsatisfactory,  and  must  necessarily  remain 
disputed  points  until  our  present  uncertain  knowledge  of  the 
chemistry  of  the  blood  proteids  becomes  fuller  and  more  definite.^ 
In  the  examination  of  a  slide  of  fresh  blood,  fibrin  appears  as 
extremely  delicate,  straight,  filamentous  lines  which  cross  and 
recross  the  field  in  every  direction.  It  forms  a  network  of  fine, 
interlacing,  fibrillary  bands,  in  the  clear  areas  of  the  serum  inter- 
vening   between    the    masses   of  corpuscles,   some  of  the  fibrin 


Normal  blood. 
Showing  rouleaux  formation  and  fibrin  network. 

threads  apparently  radiating  from  centers  consisting  of  small 
irregular  masses  of  blood-plaques.  The  relation  of  these  islands 
of  blood-plaques  to  coagulation  and  fibrin  formation,  if,  indeed, 
any  exists,  is  undetermined.  Petrone^  considers  that  the  plaques 
inhibit  rather  than  promote  these  two  processes. 

'Schafer's  "Text  Book  of  Physiology,"  vol.  i. ,  Edinburgh  and  London,  1898, 
contains  a  complete  exposition  of  the  various  theories  of  coagulation  of  the  blood  exist- 
ing up  to  the  present  time. 

2  Morgagni,  1897  ;  n.  5  and  6. 


102 


THE    BLOOD    AS    A    WHOLE. 


In   normal  blood  the  formation  of  the   fibrin 
Hyperinosis    network  becomes  apparent  within  two  or  three 
AND  minutes  after  exposure  of  the  blood  to  the  air, 

Hypinosis.  and  the  process  is  completed  within  seven  or 
eight  minutes.  In  certain  pathological  condi- 
tions, however,  both  the  length  of  time  required  for  its  formation 
and  the  density  of  the  network  varies.  An  increase  in  the 
amount  of  the  fibrin  network  is  spoken  of  as  hyperinosis,  while  a 
decrease  in  fibrin  is  termed  hypinosis. 

In  general  terms,  it  may  be  stated  that  fibrin 
Pathological  is  increased  in  acute  inflammatory^  and  infectious 
Varlations.  diseases,  especially  in  those  attended  by  an  ac- 
tive febrile  movement  and  by  exudative  proc- 
esses, the  amount  of  fibrin  roughly  corresponding  to  the  intensity 
of  the  process.  This  statement  is  made  with  certain  reserva- 
tions, for  the  rule  does  not  hold  true  in  all  such  instances,  as  is 
noted  below.  All  febrile  states  do  not,  however,  imply  a  fibrin- 
increase,  for  none  is  found  in  the  fevers  associated  with  grave 
cases  of  chlorosis  and  of  pernicious  anemia.     Hayem  ^  suggests 

Fig.  34. 


Hyperinosis. 
Showing  marked  increase  in  the  tensity  of  fibrin  network. 

that  the  density  of  the  fibrin  network  may  be  taken  as  an  indica- 
tion of  the  individual's  resisting  powers  against  disease,  inasmuch 
as  it  appears  to  be  more  marked  in  the  blood  of  the  vigorous  than 

1  "  Du  Sang,"  etc.     Paris,  1889. 


OLIGEMIA. 


103 


of  the   feeble.     In  acute  inflammations,  accompanied  by  serous 

and  purulent  exudates,  a  dense  fibrin  reticulum  is  observed,  the 

extent    of  the    exudation   being  in  a   degree  measured  by  the 

density  of  the  network.      Fibrin  is  increased  to  a  slighter  extent 

in    parenchymatous    inflammations,     in    inflammations    of    the 

mucous  membranes  and  skin,  and  in  the  febrile  stages  of  chronic 

suppurations.     Among  the  diseases  which  are  associated  with  an 

increase  in  fibrin  are  the  following  :  abscess,  pneumonia,  rheu^natic 

fever,  erysipelas,  acute  gout,  severe  angina,  bronchitis,  i^ifluenza, 

diphtheria,  pleurisy,  peritonitis,  peiicarditis,  hepatitis,  meningitis, 

acute  gastritis,  enteritis,  cystitis,  vaginitis,  pustidar  stage  of  variola, 

and   suppurating   tuberctdous  cavities.      Fibrin   is   not  increased 

in    malignant   neoplasms,    enteric  fever,    malarial  fever,   tuber- 

cidosis,  per7ncious  anemia,  leukemia,  chlorosis,  and  purpura.     In 

parenchymatous  nephritis  it  is   but  slightly  increased,  if  at   all, 

while  in  interstitial  nephritis  the  increase  may  be  notable. 

Pfeiffehr^  declares,  as  the  result  of  his  investigations,  that  in 
all  diseases  in  which  an  increase  of  fibrin  exists  inflammatory 
leucocytosis  is  also  present,  and  that  he  has  never  been  able  to 
demonstrate  hyperinosis  without  coexisting  increase  in  the  number 
of  leucocytes.  But  leucocytosis  does  not  invariably  imply  hyper- 
inosis, although  the  two  conditions  almost  always  go  hand  in 
hand,  for  leucocytosis  may  occur  in  malignant  disease  unattended 
by  fibrin  increase ;  on  the  other  hand,  in  influenza  the  fibrin  net- 
work is  denser  than  normal,  while  the  number  of  leucocytes  is 
not  increased. 

VII.     OLIGEMIA. 

The  term  oligemia  signifies  a  reduction  in  the  total  volume  of 
the  blood,  involving  a  diminution  of  both  the  liquid  and  the  cel- 
lular portions.  It  occurs  most  conspicuously  after  hemorrhage, 
and  probably  after  this  accident  only.  Sometimes  the  hemorrhage 
having  been  profuse,  the  oligemia  proves  rapidly  fatal ;  but  in 
other  instances,  where  the  hemorrhage  has  been  less  extensive, 
the  decreased  volume  of  blood  is  slowly  made  up,  first  by  a  rapid 
osmosis  of  serum  into  the  depleted  capillaries  from  the  neighbor- 
ing lymph  spaces,  and  later  by  a  slower  numerical  increase  of 
the  cellular  elements,  the  products  of  an  actual  manufacture  of 
erythrocytes  by  the  blood-making  organs. 

In  some  of  the  advanced  cachectic  states,  in  which  profound 
adynamia  and  poor  nourishment  of  the  body  are  prominent  clin- 
ical manifestations,  there  is  seemingly  good  reason  for  believing 
in  the  existence  of  a  true  oHgemia ;    but  in  the  absence  of  con- 

iZeitschr.  f.  klin.  Med.,  1897,  vol.  xxxiii.,  p.  215. 


104  THE    BLOOD    AS    A    WHOLE. 

firmatory  evidence,  reduction  of  the  blood- volume  in  this  class  of 
cases  must  remain  rather  a  suspicion  than  an  accepted  fact.  The 
term  oligemia  is,  therefore,  in  the  light  of  our  present  understand- 
ing, applicable  only  to  blood  losses  resulting  from  hemorrhage. 

VIII.     PLETHORA. 

The  term  plethora  is  currently  used  to  express  a  condition 
characterized  by  an  actual  excess  in  the  total  volume  of  the  blood, 
affecting  both  the  liquid  and  the  cellular  elements.  According 
to  the  views  of  many  of  the  older  and  a  few  of  the  modern  path- 
ologists, a  true  polyemia,  or  an  increase  in  the  blood  volume,  un- 
accompanied by  any  qualitative  changes,  is  thought  to  exist  in 
certain  individuals  whose  mode  of  life  and  luxurious  habits  are 
supposed  to  predispose  and  give  rise  to  excessive  blood-forma- 
tion. The  compatibility  between  a  real  fuU-bloodedness  and 
a  **high-Hver"  was  formerly  much  more  generally  credited  than 
at  the  present  time,  and  the  association  of  such  signs  as  a  rich, 
ruddy  complexion,  enlargement  of  the  superficial  blood-vessels, 
and  a  full,  bounding  pulse  was  depended  upon  for  the  recognition 
of  this  condition.  Of  late,  however,  the  drift  of  opinion  is  against 
the  probability  of  any  such  permanent  increase  in  blood  volume, 
but  until  an  accurate  method  of  estimating  the  total  quantity  of 
blood  in  the  body  has  been  devised,  the  presence  or  absence  of  a 
real  plethora  must  obviously  remain  conjectural. 

True  plethora  may  occur  as  a  transitoiy  condition,  as  the  re- 
sult of  the  direct  transfusion  of  blood,  or  the  mechanical  forcing 
back  into  the  general  circulation  of  a  quantity  of  blood  from  a 
part  to  be  removed  from  the  body,  as  by  the  use  of  an  Esmarch 
rubber  bandage  previous  to  the  amputation  of  a  limb  ;  in  a  similar 
manner,  a  new-born  infant  may  become  temporarily  plethoric  by 
a  complete  emptying  of  the  placenta  before  tying  the  umbilical 
cord.  Plethora  resulting  from  any  of  these  influences  is  invari- 
ably of  a  transient  character,  for  the  physiological  balance  of  the 
organism  rapidly  disposes  of  the  surplus  amount  of  blood,  by  de- 
struction of  the  excess  amount  of  cellular  elements  and  by  the 
elimination  of  the  liquid  portions. 

Serous  plethora  may  be  defined  as  an  increase  in  the  volume  of 
blood  due  to  excessive  quantities  of  its  liquid  and  saline  con- 
stituents, without  augmentation  in  the  number  of  its  cellular 
elements.  A  condition  of  this  sort  may  be  dependent  upon  the 
ingestion  of  large  amounts  of  liquids,  upon  the  transfusion  of  saline 
solutions,  or  upon  vaso-motor  dilatation,  whereby  the  transfer 
of  an  unduly  large  amount  of  liquids  from  the  tissues  to  the  blood- 


HYDREMIA.  IO5 

vessels  is  promoted.  In  organic  lesions  of  the  kidneys  and  of  the 
heart,  with  diminished  elimination  of  water  from  the  system,  a 
serous  plethora  of  more  or  less  chronicity  may  develop.  The 
condition,  however,  is  usually  of  transient  duration,  as  the  surplus 
liquids  in  the  circulatory  system  are  quickly  disposed  of,  and  the 
blood  volume  reduced  to  normal,  by  intracapillary  transudation. 
Cellular  plethora  is  a  term  which  may  appropriately  be  applied 
to  the  condition  also  known  as  polycythemia^  consisting  in  an  in- 
crease in  excess  of  the  normal  standard  in  the  number  of  erythro- 
cytes. The  circumstances  under  which  this  change  occurs  will 
be  discussed  later.     (See  page  149.) 

IX.     HYDREMIA. 

A  relative  increase  in  the  quantity  of  liquid  constituents  of  the 
blood  is  known  as  hydremia.  This  condition  must  not  be  con- 
fused with  serous  plethora,  which  is  characterized  by  both  a 
relative  and  absolute  increase  in  the  liquids  of  the  blood.  The 
specific  gravity  of  the  blood  is  observed  to  fall  in  relation  to  the 
degree  to  which  the  change  develops. 

Hydremia  may  be  produced  by  any  factors  which  disturb  the 
normal  relations  between  the  cellular  and  the  liquid  elements  of 
the  blood,  so  that  the  latter  are  unduly  increased.  In  other 
words,  the  blood  is  diluted,  in  consequence  of  which  a  given  drop 
of  such  blood  shows  an  apparent  decrease  in  the  number  of  cel- 
lular elements,  although  the  latter  are  in  reality  unaffected  by  the 
change.  Hydremia  is  observed  after  extensive  heuiorrhages,  in 
which  the  primary  effect  of  the  oligemia  is  the  taking  up  by  the 
capillaries  of  an  excess  of  tissue-fluids,  to  replace  the  blood  loss  ; 
later,  as  blood-formation  gradually  makes  up  for  the  cellular 
deficiency,  the  normal  ratio  between  the  corpuscles  and  the  plasma 
is  reestablished.  Hydremia  may  also  occur  as  the  result  of  the 
ingestion  of  large  amounts  of  liquids,  after  the  injectio?i  of  normal 
saline  sohitioji,  and  as  a  consequence  of  vaso-motor  dilatation. 
The  watery  constituents  of  the  blood  are  relatively  increased  in 
certain  of  the  severe  anemias,  owing  to  the  deficiency  of  corpus- 
cular elements,  which  is  compensated  by  fluids  derived  from  the 
tissues.  In  some  dropsical  conditions,  notably  those  associated 
with  renal  and  cardiac  lesions,  hydremia  may  also  be  said  to  exist, 
either  with  or  without  anemia.  Hydremia,  while  it  does  not 
necessarily  imply  the  coexistence  of  anemia,  is  naturally  often  an 
accompaniment  of  the  latter  condition. 

Hydremia  dependent  upon  such  physiological  factors  as  inges- 
tion of  fluids  and  vaso-motor  dilatation  is  a  transient  condition,  for 


I06  THE    BLOOD    AS    A    WHOLE. 

the  excess  amount  of  fluid  is  promptly  eliminated,  and  the  normal 
relations  restored.  In  other  conditions  the  duration  of  the  change 
obviously  depends  upon  the  nature  and  permanency  of  the  etiolog- 
ical factor  or  factors. 

X.     ANHYDREMIA. 

Ajihydremia  is  a  condition  in  which  a  relative  diminution  in 
the  liquid  constituents  of  the  blood  occurs,  as  the  result  of  rapid 
osmosis  from  the  capillaries  into  the  surrounding  tissue.  Inas- 
much as  the  cellular  elements  do  not  share  in  this  draining-away, 
their  number  is  necessarily  increased  in  a  given  drop  of  such  con- 
centrated blood.  The  specific  gravity  of  the  blood  increases  in 
relation  to  the  severity  of  the  fluid  drain. 

Conditions  which  cause  the  sudden  dissipation  of  large  quanti- 
ties of  liquids  from  the  body,  in  consequence  of  hyperactivity  of 
the  mucous  and  serous  surfaces,  are  the  most  prominent  factors 
in  producing  anhydremia.  Thus,  after  profuse  diarrheas,  urinary 
crises,  free  szveatvig,  excessive  vomiting,  and  sudden  and  exten- 
sive pleural  and  peritoneal  effusions  the  blood  becomes  concen- 
trated from  a  temporary  loss  of  its  fluid  elements,  which  pass 
from  the  vessels  into  the  tissues  to  replace  the  Hquids  lost  in 
consequence  of  the  drain, 

Oliver^  has  shown  also  that  a  moderate  degree  of  anhydremia 
may  arise  as  the  result  of  various  influences  which  cause  an  in- 
crease in  arterial  tension,  and  a  consequent  acceleration  in  the 
transfer  of  water  from  the  vessels  into  the  tissues.  For  example, 
the  change  has  been  brought  about  by  the  influence  of  local  and 
general  exercise,  far'adism,  massage,  cold  bathing,  and  the  admin- 
istration o{  snpra-renal  extract. 

From  the  nature  of  the  drain,  which  is  rapidly  compensated  by 
the  constant  interchange  which  goes  on  between  the  \^essel-  and 
the  tissue-fluids,  anhydremia  is  a  temporar^^  condition.  A  per- 
fect physiological  balance  limits  its  duration  to  brief  periods  of 
time.     (See  "  Polycythemia,"  p.  149.) 


XI.     LIPEMIA. 

Fat  is  present  in  normal  blood,  in  the  form  of  an  exceedingly 
fine  emulsion,  the  amount  vaiy^ing  in  man  from  i.oo  to  3.25  parts 
per  1,000  of  blood,  the  mean  amount  being  1.6,  according  to  the 
analyses  of  Becquerel  and  Rodier.  - 

^Croonian  Lectures,  Lancet,  1896,  vol.  i.,  pp.  1541,  1621,  1699  and  1778. 
2 Cited  by  Futcher:  Journ.  Am.  Med.  Assn.,  1899,  vol.  xxxiii.,  p.  1006. 


MELANEMIA.  10/ 

By  the  term  lipemia  is  meant  the  presence  of  an  excess  of  free 
fat  in  the  circulating  blood,  a  phenomenon  which  is  observed  in  a 
number  of  conditions,  both  physiological  and  pathological.  Thus, 
the  blood  may  contain  a  sufficient  amount  of  fat  to  give  rise  to 
temporary  lipemia  during  the  period  of  digestion,  especially  after 
a  meal  rich  in  fats  ;  the  condition  may  be  also  met  with  in  the 
bi'east-fed  infant,  in  the  pregnant  woman,  and  in  the  obese. 
Menstrual  suppressioji  may  also  give  rise  to  a  similar  excess  of 
fat  in  the  blood. 

The  existence  of  lipemia  is  of  little  clinical  importance,  for  it 
has  been  observed  in  a  number  of  diseases,  so  that  it  cannot  be 
considered  characteristic  of  any  particular  lesion.  It  has  been 
noted  in  the  following  conditions  :  chronic  alcoholism,  diabetes 
mellitus,  certain  diseases  of  the  liver,  heart,  and  pancreas,  .chronic 
nephritis,  splenitis,  tuberculosis,  malarial  fever,  typJius  fever,  Asiatic 
cholera,  and  poisonijig  by  phosphorus  and  by  carbon  monoxide. 
Lipemia  commonly  occurs  as  the  result  of  lacerated  wounds  of  the 
blood-vessels  situated  in  fatty  tissues,  and  after  fractures  of  the 
lojig  bones  involving  injury  of  the  fatty  marrow. 

The  degree  of  lipemia  may  be  so  marked  that  the  macroscop- 
ical  appearance  of  the  fresh  blood  is  altered,  the  presence  of  large 
quantities  of  free  fat  rendering  it  turbid  and  milky.  This  is  es- 
pecially conspicuous  in  the  specimen  of  blood-serum  obtained  by 
centrifugalization,  which  has  a  distinct  grayish,  opaque  appear- 
ance, not  unlike  chyle. 

Macroscopically,  the  presence  of  lipemia  may  be  determined ' 
by  mixing  with  ether  in  a  test-tube  a  portion  of  the  turbid  blood- 
serum,  the  excess  of  fat  promptly  dissolving,  so  that  the  serum 
becomes  clear. 

Microscopically,  lipemia  may  be  recognized  by  the  presence 
of  large  numbers  of  glistening  fat-droplets,  about  .  5  to  2  //  in  di- 
ameter, which  lie  free  in  the  plasma  between  the  groups  of  cor- 
puscles, often  exhibiting  very  lively  Brownian  movements.  These 
droplets  respond  to  the  usual  tests  for  fat,  dissolving  in  ether, 
and  staining  black  with  osmic  acid,  and  brick-red  with  Sudan  III. 

XII.     MELANEMIA. 

The  occurrence  in  the  circulating  blood  of  minute  particles  of 
melanin  or  pigment,  derived  usually  from  the  hemoglobin  of  the 
red  blood  corpuscles  destroyed  by  blood  parasites,  is  known  as 
melanemia.  These  melanin  particles  appear  as  fine  bits  of  granu- 
lar matter,  of  a  reddish-yellow  or  black  color,  either  lying  free  in 
the  blood-plasma,  or  embedded  in  the  protoplasm  of  the  leuco- 


I08  THE    BLOOD    AS    A    WHOLE. 

cytes.  In  some  instances  the  granules  are  extremely  small-sized 
and  few  in  number,  and  again  the  amount  may  be  considerable, 
numbers  of  pigment  particles  being  apparently  fused  into  masses. 
Melanemia  is  frequently  present  in  malarial  fever,  especially 
of  the  severer  types,  both  in  the  form  of  free  pigment,  and  as 
pigmented  leucocytes.  Particles  of  pigment  in  the  bodies  of  the 
leucocytes  have  also  been  seen  in  relapsing  fever,  in  melanotic 
sarcoma,  and  in  Addisoii  s  disease. 


XIII.     GLYCEMIA. 

Glycemia,  or  the  presence  in  the  blood  of  grape-sugar,  occurs 
in  perfectly  normal  blood  to  a  ver}'  slight  degree,  the  quantity  of 
sugar  found  under  physiological  circumstances  not  exceeding  1.5 
parts  per  thousand.  The  presence  of  sugar  in  excess  of  this  fig- 
ure, which  may  be  termed  Jiyperglycemia,  is  met  with  in  diabetes 
mellitus,  in  which  disease  as  high  as  9  parts  per  thousand  hav^e 
been  detected.^  The  investigations  of  Freund-  and  of  Trinkler^ 
apparently  show  that  the  blood  in  carcinoma,  especially  of  vis- 
ceral involvement,  contains  an  excess  of  some  reducing  agent,  to 
all  intents  and  purposes  identical  with  sugar.  The  former  author, 
in  consequence  of  this  fact,  lays  stress  on  the  finding  as  a  means 
of  differentiating  between  carcinoma  and  sarcoma,  since  no  such 
increase  has  been  observed  as  an  accompaniment  of  the  latter 
type  of  neoplasm. 

The  most  accurate  method  of  detecting  small  quantities  of 
sugar  in  the  blood  is  by  the  phenyl-hydrazin  hydrochloride 
test,  conducted  by  von  Jaksch  ^  as  follows  : — A  small  amount  of 
blood,  obtained  by  wet-cupping,  is  first  freed  from  proteids,  by 
adding  an  equivalent  weight  of  sodium  sulphate,  and  then  boil- 
ing, and  filtering,  the  filtrate  thus  obtained  being  used  for  the 
test.  A  solution  is  now  made  in  a  test-tube,  by  mixing  2 
parts  of  phenyl-hydrazin  hydrochloride  and  4  parts  of  sodium 
acetate  with  about  6  cubic  centimeters  of  water,  and  gently 
heating  the  fluid,  if  necessan,^,  to  effect  solution.  Five  cubic 
centimeters  of  the  proteid-free  filtrate,  while  still  warm,  are 
added  to  an  equal  volume  of  the  test-solution.  This  mixture  is 
then  placed  in  a  test-tube  half  filled  with  water,  heated  for  half 
an  hour  in  a  water-bath,  and  allowed  to  stand  until  cool.  When 
cooling  of  the  mixture   has  occurred,  it  shows  under  the  micro- 

1  Hoppe-Seyler :  Virchow's  Archiv.,  1S58,  vol.  xiii.,  p.  104. 
2Wien.  med.  Blatter,  1885,  vol.  viii.,  pp.  268  and  873. 
3  Central bl.  f.  d.  med.  ^Vissensch.,  1890,  vol.  xxviii.,  p.  498. 
*  Zeitschr.  f.  klin.  Med.,  1886,  vol.  xi.,  p.  20. 


URICACIDEMIA.  IO9 

scope  the  presence  of  the  characteristic  yellowish  crystals  of 
phenyl-glucosazon,  either  detached  or  in  clusters,  together  with 
colorless  crystals  of  sodium  sulphate. 


XIV.     URICACIDEMIA. 

The  presence  in  the  blood  of  a  demonstrable  amount  of  uric 
acid  has  been  designated  as  uric  acidemia.  The  blood  of  the 
normal  individual  does  not  contain  this  substance  in  amounts 
sufficiently  large  to  be  detected  by  ordinary  clinical  tests,  but  it  is 
found  in  appreciable  quantities  in  a  number  of  pathological  condi- 
tions. Garrod  ^  many  years  ago  recognized  that  excessive  accumu- 
lation of  uric  acid  in  the  blood  was  associated  with  ^(9?//,  and  he  at- 
tached to  this  sign  much  diagnostic  significance.  Later  investiga- 
tions, however,  have  proved  the  utter  unreliability  of  this  finding 
as  a  pathognomonic  sign  of  this  disease,  for  in  recent  years  a  large 
number  of  other  conditions  have  been  found  to  be  more  or  less 
constantly  accompanied  by  relatively  large  amounts  of  uric  acid 
in  the  circulating  blood.  Notable  examples  of  such  diseases  are 
pneumonia,  hepatic  cirrhosis,  acute  and  chronic  nephritis,  chronic 
gastritis,  leukemia,  severe  anemia,  and  those  conditions  in  which 
deficient  blood  aeration  constitutes  a  prominent  clinical  symptom, 
such  as  organic  cardiac  disease,  exudative  pleurisy,  and  emphysema. 
Uric  acid  is  not  found  in  the  blood  in  enteric  fever,  and  in  rheu- 
matic fever.  Pyrexia,  of  itself,  evidently  has  no  influence  in  pro- 
ducing uricacidemia,  nor  is  it  at  all  probable  that  this  condition 
goes  hand  in  hand  with  an  excessiv^e  elimination  of  uric  acid  in 
the  urine. 

Garrod's  test  is  well  adapted  clinically  for  detecting  the  pres- 
ence of  appreciable  quantities  of  uric  acid  in  the  blood.  Slightly 
modified,  it  may  be  applied  in  the  following  manner : — Two  and 
one-half  cubic  centimeters  of  blood-serum,  obtained  by  blistering, 
are  placed  in  a  shallow  watch  glass,  and  acidulated  by  the  addi- 
tion of  about  4  drops  of  a  30  per  cent,  aqueous  solution  of  acetic 
acid.  A  Hnen  thread  is  then  immersed  in  the  acidulated  blood, 
which  is  slowly  evaporated  at  a  temperature  not  exceeding  70° 
F.  At  the  expiration  of  from  twenty-four  to  fort>^-eight  hours, 
if  the  sample  of  blood  contains  uric  acid,  characteristic  crystals 
of  this  substance  are  deposited  upon  the  thread,  their  identity 
being  readily  detected  by  microscopical  examination,  and  by  the 
murexide  test. 

'Med.  and  Chirurg.  Trans.,  1854,  vol.  xxxvii.,  p.  49.  Also,  Ibid.,  1848,  vol. 
xxxi.,  p.  183. 


no  THE    BLOOD    AS    A    WHOLE. 


XV.     CHOLEMIA. 


The  presence  in  the  blood  of  bile  or  bile-pigments  has  been 
termed  cholemia,  a  condition  which  accompanies  various  forms 
of  icterus.  Bilious  blood  may  have,  as  already  stated,  a  yellow- 
ish-red color,  and  may  yield  on  agitation  an  abundant  foam,  tinged 
with  yellow.  Bilirubin  may  be  detected  in  the  blood  even  when 
urine  tests  for  this  substance  have  proved  negative,  according  to 
von  Jaksch,^  who  employs  this  procedure  to  demonstrate  its  pres- 
ence : — About  lO  cubic  centimeters  of  blood,  obtained  by  wet- 
cupping,  are  allowed  to  clot,  after  which  the  serum  is  pipetted 
off,  filtered  through  asbestos,  and  coagulated  at  a  temperature  of 
80°  C.  Thus  treated,  the  presence  of  bilirubin  is  betrayed  by  a 
greenish  discoloration  of  the  serum,  which,  if  bile-free,  remains  a 
pale  straw  color.  Should  a  brownish  color  develop  by  this  test, 
the  presence  of  hemoglobin  in  the  serum  is  indicated. 

XVI.     ACETONEMIA   AND   LIPACIDEMIA. 

The  occurrence  in  the  blood  of  demonstrable  amounts  of  ace- 
tone and  of  fatty  acids  are  referred  to  as  acetonemia  and  lipaci- 
demia,  respectively.  Acetonemia  has  been  found  in  associa- 
tion with  numerous  pathological  conditions,  chiefly  in  those 
characterized  hy  pyrexia,  while  fatty  acids  in  the  blood  have  been 
detected  in  diabetic  coma,  in  malignant  janndice,  in  leukemia, 
and  in  various  acute  infections. 

For  the  recognition  of  acetone  Simon"  recommends  Den- 
nige's  test,  to  be  applied  as  follows  : — About  3  cubic  centimeters 
of  blood  are  treated  with  30  cubic  centimeters  of  Dennige's 
reagent  (  20  grammes  of  concentrated  sulphuric  acid  mixed  with 
100  cubic  centimeters  of  distilled  water,  to  which  5  grammes 
of  yellow  oxide  of  mercury  are  then  added),  and  allowed  to  stand 
until  a  dark  brown  precipitate  has  formed,  after  which  the 
supernatant  fluid  is  filtered  off,  and  treated  with  more  of  the 
reagent,  so  as  to  effect  complete  precipitation.  It  is  then  acidi- 
fied by  the  addition  of  about  3  cubic  centimeters  of  a  30  per 
cent,  solution  of  sulphuric  acid,  and  boiled  for  one  or  two  min- 
utes. The  appearance  of  a  white  precipitate  on  boiling  indicates 
the  presence  of  acetone.  This  precipitate  may  be  almost  wholly 
dissolved  by  the  addition  of  hydrochloric  acid  in  excess. 

Fatty  acids  may  be  detected  by  boiling  equal  parts,  by  weight, 
of  blood  and   sodium  sulphate,  filtering,  evaporating  the  filtrate 

•  Loc.  cit. 

2**  Clinical  Diagnosis,"  Phila.,  1901  (3d  ed. ). 


BACTERIEMIA.  I  I  I 


to  diyness,  and  then  extracting  the  residue  with  absolute  alcohol. 
Microscopical  examination  of  the  residue  will  reveal  crystals  of 
fatty  acids,  if  lipacidemia  exists. 


XVII.     BACTERIEMIA. 

Bacteriania,  or  the  presence  of  bacteria  in  the 
Occurrence,  circulating  blood,  is  a  condition  associated  with 
a  number  of  infectious  diseases,  in  which  instances 
it  is  frequently,  but  by  no  means  constantly,  possible  to  dis- 
cover the  specific  micro-organism  of  the  disease  in  question  by 
careful  bacteriological  examination  of  the  blood.  The  demonstra- 
tion in  the  blood,  even  if  it  is  possible  only  in  occasional  instances, 
of  such  bacteria  as  pyogenic  cocci  and  pneinnococci  in  septic  dis- 
eases, of  the  streptococcus  pyogenes  and  other  pyogenic  organisms 
in  malignant  endocarditis,  of  the  bacillus  of  Eberth  in  enteric 
fever,  of  the  gonococcus  in  gonorrheal  rheumatism,  and  of  the 
bacillus  tuberculosis  in  severe  cases  of  acute  miliary  tuberculosis, 
is  sufficient  proof,  without  citing  other  instances,  of  the  diag- 
nostic value  of  bacteriological  blood  examinations,  which  are 
warranted  in  every  case  of  severe  infection  the  nature  of  which 
appears  doubtful. 

From  the  clinician's  viewpoint,  normal  blood 
Latent  is  absolutely  sterile,  since  no  cultural  method  has 
Infection,  yet  been  devised  by  which  it  is  possible  to  demon- 
strate the  presence  of  bacteria  in  the  circulation 
of  the  healthy  individual.  From  the  pathologist's  standpoint, 
however,  such  a  statement  must  be  guardedly  accepted,  in  the 
light  of  recent  investigations.  Adami,^  in  a  recent  brilliant  resume 
of  the  whole  field  of  bacterial  infection,  cites  a  series  of  apparently 
conclusive  experiments  by  his  assistants,  Nicholls  and  Ford,  who 
found  that  the  kidneys  and  livers  of  healthy  animals,  removed 
aseptically  immediately  after  death  and  placed  in  agar-agar  kept 
at  the  temperature  of  the  body,  showed  after  a  few  days  a  rela- 
tively abundant  growth  of  bacteria.  This  observer  concludes 
that  under  normal  conditions  the  leucocytes  pass  out  through 
the  mucosa  on  to  the  free  surface  of,  more  especially,  the  alimen- 
tary tract,  some  of  these  cells  then  undergoing  destruction,  while 
others,  now  laden  with  various  foreign  matter,  including  bacteria, 
pass  back  again  into  the  submucosa  and  find  their  way  either 
into  the  lymphatic  channels  or  into  the  portal  venules.  In  both 
of  these  sites  there  exists  a  decided  tendency  toward  bacterial 
disintegration  and  destruction.     Such  isolated   bacteria  as  may 

ijour.  Am.  Med.  Assn.,  1899,  vol.  xxxiii.,  pp.  1509  and  1572. 


112  THE    BLOOD    AS    A    WHOLE. 

have  escaped  leucocytal  destruction  or  removal  b}'  the  lymphatic 
glands  or  by  the  endothelium  of  the  portal  system,  may  pass 
either  through  the  thoracic  duct  or  through  the  liver,  and  enter 
the  systemic  circulation,  from  which  they  are  eliminated  chiefly 
by  the  kidneys.  Such  a  condition  as  this,  known  as  "  latent  in- 
fection "  or  ''latent  microbism,"  appears  to  be  compatible  with 
perfect  health,  for  the  number  of  bacteria  which  thus  gain  access 
to  the  blood-stream  and  tissues  is  so  small  that  unless  their 
virulence  is  especially  striking  and  the  susceptibility  of  the  indi- 
vidual peculiarly  marked,  the  resisting  powers  of  the  tissues  re- 
main sufficiently  strong  to  prevent  bacterial  proliferation.  It  is 
also  obvious  that  the  presence  in  the  blood  of  such  a  Hmited 
number  of  bacteria  cannot  be  demonstrated  by  culturing. 

If,  on  the  other  hand,  the  conditions  are  such 
Blood         that  bacteria  multiply  in  the  blood  to  any  decided 

Cultures,  extent,  then  their  development  in  artificial  media 
outside  the  body  may  be  successfully  obtained  in 
many  instances,  provided  that  proper  technique  is  employed. 
That  this  has  not  been  more  successfully  accomplished  is  no 
doubt  due  to  the  powerful  bactericidal  action  of  the  shed  blood, 
whereas  this  influence  in  the  circulating  blood  is  but  trifling.  As 
Adami  remarks,  "  Because  certain  observers  have  failed  to  dis- 
cover bacteria  in  the  blood  from  cases  of  infectious  diseases,  it  by 
no  means  follows  that  the  blood  when  shed  has  been  free  from 
bacteria."  Therefore,  it  seems  fair  to  presume  that  if  precautions 
are  taken  to  attenuate  the  bactericidal  properties  of  the  shed 
blood,  by  freely  diluting  it  with  a  large  quantity  oi  fluid  media, 
instead  of  using  relatively  small  amounts  of  solid  culture,  as  has 
been  done  largely  in  the  past,  blood  culturing  will  yield  a  much 
higher  percentage  of  positive  findings,  and  will  give  more  uniform 
results.     (See  "  Bacteriological  Examination,"  page  83.) 

Among  the  various  bacteria  which  different 
Bacterla.  observers  have  succeeded  in  isolating  from  the 
Found  in       circulating  blood  are  included  manv  micro-ors^an- 

THE  Blood,     isms,  the  identity  of  which  as  etiological  factors 

of  disease  is    generally  recognized,  and    also  a 

number  to  which  pathogenicity  cannot  be  convincingly  attributed. 

The   following  list   gives   the  most  important  examples   of  the 

former  class  : 

B.  ant/wacis. 

B.  coli  coinnuinis. 

B.  ijifliicnzce. 

B.  leprcB. 

B.  mallei. 


ANEMIA.  I  I  3 

B.  pestis  bubofiicce. 

B.  tetani. 

B.  tuberculosis. 

B.  typhosus. 

Diplococcus  iniracellularis  meningitidis. 

Gonococcus. 

Pneumococcus. 

Pyogenic  staphylococci. 

Pyogenic  streptococci. 

In  addition  to  this  list,  a  certain  amount  of  interest  attaches  to 
the  discovery  in  the  blood  of  certain  bacilli  (Achalme),  and  diplo- 
cocci  (Triboulet)  in  rheumatic  fever  ;  of  peculiar  bacilli  (Afanassiew) 
in  relapsing  fever,  in  addition  to  the  specific  spirillum  of  this  in- 
fection ;  oi diplobacilli  (Crdiig)  in  mumps  ;  and  of  diplococci  (CIslss)  in 
scarlet  fever,  and  in  typhus  fever  (Balfour  and  Potter),  The  exact 
significance  of  finding  the  bacillus  icteroides  (Sanarelli)  in  the  blood 
of  yellow  fever  patients  is  still  a  current  topic  of  discussion. 

The  conditions  in  which  the  above-named  bacteria  occur  in  the 
blood  will  be  discussed  in  a  later  section,  under  the  diseases  in 
question.      (See  **  General  Hematology.") 

XVIII.     ANEMIA. 

In  a  clinical  sense,  the  term  anemia  refers  to 
Definition,  any  deterioration  in  the  quality  of  the  blood,  af- 
fecting either  the  erythrocytes,  the  hemoglobin, 
or  both  of  these  elements.  Thus,  in  pernicious  anemia  the  most 
conspicuous  deterioration  in  the  quality  of  the  blood  is  a  diminu- 
tion in  the  number  of  erythrocytes,  or  an  oligocythemia;  in 
chlorosis,  the  most  marked  change  is  usually  a  loss  of  hemo- 
globin, or  an  oligochromemia ;  while  in  many  other  anemic  con- 
ditions the  erythrocytes  and  hemoglobin  are  decreased  more  or 
less  proportionately.  While  it  is  true  that,  strictly  speaking, 
the  word  anemia  may  also  be  used  to  designate  a  reduction  in 
the  blood  volume,  this  condition  is  better  defined  by  the  use  of 
the  term  oligemia.  Ischemia  is  a  form  of  local  anemia  resulting 
from  some  mechanical  interference  with  the  blood  supply  of  the 
affected  area. 

In  certain  individuals  with  such  decided  pallor 

PsEUDO-        of  the  skin  and  mucous  membranes  that  their 

Anemia.        appearance  at  once  leads  one  to  infer  that  they 

are  suffering  from  a  well-defined  anemia,  no  signs 

of  this  condition  can  be  discovered,  for  even  after  the  most  careful 

examination  of  the  blood,  the  number  of  erythrocytes  and  the  per- 

8 


114  THE    BLOOD    AS    A    WHOLE. 

centage  of  hemoglobin  may  be  found  to  be  normal.  Such  instances 
of  apparent  blood  deterioration  have  been  called  pseudo-anemia  ; 
they  are  often  explained  by  hereditary'  peculiarities,  by  vaso- 
motor disturbances  affecting  the  superficial  capillaries,  and  by 
deficiencies  in  the  pigment  and  in  the  development  of  the  capillary 
network  of  the  skin.  Dwellers  in  tropical  countries  are  especially 
prone  to  this  spurious  form  of  anemia,  to  which  the  misnomer  tropi- 
cal anemia  is  occasionally  applied.  Every  medical  clinic  can  furnish 
patients  suffering  from  neurasthenia,  tuberculosis,  and  advanced 
Bright's  disease,  whose  pallid  countenances  are  a  striking  con- 
trast to  their  normal  blood-counts.  It  does  not  follow,  there- 
fore, that  pallor  of  the  skin  and  mucous  membranes  is  invariably 
an  indication  of  anemia,  although  this  sign  is  not  misleading 
in  the  majority  of  instances.  On  the  other  hand,  it  should  not 
be  forgotten  that  persons  of  good  color  and  robust  appearance 
sometimes  suffer  from  decided  anemias  without  the  fact  becoming 
evident  at  first  glance.  In  view  of  these  sources  of  error,  in 
order  to  diagnose  anemia  with  absolute  accuracy,  an  examination 
of  the  blood  is  essential,  for  no  matter  how  valuable  other 
clinical  signs  may  appear,  the  changes  in  the  blood  are  often  the 
real  key  to  the  situation. 

An   entirely  satisfactor)^   classification    of   the 
Classifi-       various  forms   of  anemia  still  remains  to  be  de- 
CATION.         vised,  in  spite  of  the  numerous  attempts  which  not 
a  few  eminent  authorities  have  made  to  group  these 
conditions  according  to  sound  pathological  considerations.    There- 
fore, largely  for  the  sake  of  convenience,  all  anemias  may  be  broadly 
grouped  into  two  theoretical  classes  :  primary  and  secondary. 

According  to  this  tentative  classification,  primary  anemias  may 
be  considered  those  in  which  a  lesion  of  the  hematopoietic  organs 
is  essentially  accountable  for  the  production  of  the  disease.  In 
anemias  of  this  sort,  the  etiological  factors  are  either  entirely 
undiscoverable,  or,  if  they  are  to  be  detected,  too  trivial  to  explain 
the  intensity  of  the  disease.  Here  the  predominant  clinical 
manifestations  are  to  be  found  in  the  changes  occurring  in  the 
composition  of  the  blood,  the  other  symptoms  being  considered 
secondary  to,  and  dependent  upon,  these  alterations. 

Under  the  term  secondary  ajiemia  are  included  those  cases 
of  anemia  which  are  apparently  secondary  to,  and  symp- 
tomatic of,  certain  definite  pathological  lesions  not  primarily 
affecting  the  blood-making  organs,  such  as,  for  example,  enteric 
fever,  syphilis,  tuberculosis,  malignant  disease,  malarial  fever,  and 
hemorrhage.  In  such  anemias  the  other  clinical  symptoms  are, 
as  a  rule,  much  more  conspicuous  than  the  blood-changes,  which 


ANEMIA. 


115 


are  thought  to  be  secondary.  An  exception  to  this  general  rule 
must  be  taken,  however,  in  regard  to  the  anemia  caused  by  the 
presence  of  the  bothriocephalus  latus  in  the  intestinal  canal,  for 
in  this  infection  the  blood-picture  is  by  all  odds  the  most  striking 
clinical  manifestation.  It  is,  furthermore,  true  that  in  some 
instances  a  secondary  anemia  may  apparently  merge  into  one  of 
the  primary  type,  should  the  protracted  duration  of  the  former 
in  course  of  time  cause  such  profound  systemic  effects  that  finally 
the  blood-making  organs  become  exhausted,  and  refuse  ade- 
quately to  supply  the  constant  demand  for  corpuscles,  with  the 
result  that  the  most  prominent  clinical  signs  now  are  found  in 
the  blood,  and  not  in  the  original  symptoms  of  the  disease  in 
question.  The  high-grade  anemia  which  sometimes  follows 
enteric  fever,  becoming  of  such  intensity  that  it  counterfeits  a 
primary  anemia,  may  be  cited  as  an  example  of  this  change. 

Until  further  progress  has  been  made  in  the  study  of  the  phys- 
iology and  pathology  of  the  blood-making  organs,  the  following 
provisional  classification  of  the  anemias  may  be  used  for  clinical 
purposes  : — 

I.  Primary  Anemia.  Chlorosis,  pernicious  anemia  ^splenic  anemia, 
lymphatic  leukemia,  spleno-medullary  leukemia,  Hodgkin's  disease. 

II.  Secondary  Anemia.  Dependent  upon  causes  such  as 
hemorrhage,  intestinal  parasites,  prolonged  lactation,  unfavorable 
hygiene,  metal  poisoning,  malig?iant  disease,  acute  infections,  a?id 
chronic  diseases  producing  long-standing  drains  on  the  albumi- 
noids of  the  blood. 

Excluding  the  effects  of  hemorrhage,  deficient 
Pathogenesis,  blood  formation,  excessive  blood  destruction,  and 
a  combination  of  these  two  processes  are  generally 
regarded  as  the  three  possible  essential  factors  in  the  production 
of  anemia.  Deficient  hemogenesis  is  to  be  attributed  to  a  large 
number  of  different  causes,  among  the  most  prominent  of  which 
may  be  mentioned  the  influence  of  unhygienic  surroundings, 
and  insufficient  nourishment  from  improper  food  and  from 
inadequate  powers  of  assimilation.  It  is  also  probable  that  con- 
genital and  acquired  failure  of  the  blood-making  organs,  and  the 
presence  of  growths  which  intercept  the  material  for  blood  forma- 
tion are  to  be  considered  as  the  origin  of  defective  hemogenesis  in 
some  instances.^  Excessive  blood  destruction  may  be  due  to 
acute  febrile  and  infectious  conditions,  or  to  the  presence  in  the 
blood  of  certain  toxines  which  destroy  the  corpuscles.  It  is 
characterized  during  life  by  an  excess  of  urobilin  and  iron  in 
the  urine,  and  by  the  development  of  hematogenous  jaundice. 

1  Mackenzie:   Lancet,  1891,  vol.  i.,  p.  73. 


SECTION    III. 


HEMOGLOBIN,  ERYTHROCYTES,    BLOOD   PLAQUES, 

AND    HEMOCONIA. 


( Triacid  Stain. ) 
Fig.  1.     Normal  Erythrocytes. 

Fig.  2.     Erythroblasts. 

1.  Microblast.    Note  the  dense,  glistening  nucleus,  and  the  scanty,  ragged  zone  of  proto- 

plasm. .       .  ,      , 

2,  3,  4,  5,  6.   Normoblasts.    The  process  of  partial  nuclear  extrusion  is  apparently  shown 

'in  3  and  s;  in  the  latter  cell  the  basic  affinity  of  the  nucleus  is  singularly  slight.  The 
cell,  6,  while  as  large  as  many  megaloblasts,  retains  the  nuclear  characteristics  of  the 
normoblast,  of  which  it  represents  perhaps  a  hydropic  form.  Some  writers  regard 
such  ervthroblasts  as  megaloblasts,  on  account  of  their  large  size. 
7,  8,  9,  lo,  II,  12,  13.  Megaloblasts.  In  7  the  nucleus,  while  normoblastic  in  size,  is 
megaloblastic  in  structure  and  in  staining  affinity.  Note  the  variation  in  the  size  of 
these  cells,  their  delicate  nuclear  chromatin,  and  their  decided  tendency  toward 
polychromatophilia.  In  all  the  nucleus  and  protoplasm  are  separated  by  a  conspicu- 
ous hyaline  ring. 

Fig.  3.     Erythroblasts  with  Multiple  Nuclei. 

1.  Cell  with  a  constricted,  convoluted   nucleus,  apparently  undergoing  solution  in  the 

protoplasm. 

2.  Normoblast  with  three  nuclei  arranged  somewhat  in  the  form  of  a  clover-leaf. 

3.  Cell  with  two  large  nuclei,  each  apparently  in  an  early  stage  of  extrusion.     Note  the 

affinity  for  fuchsin  displayed  by  the  protoplasm  and  by  the  upper  nucleus,  and  the 
distinct  hyaline  zone  encircling  the  lower  one. 

4.  5.   Normoblasts  in  IcarAokinesis. 

Fig.  4.     Erythrocytes  Deformed  in  Shape  and  Size. 
I,  2.   Microcytes. 

3.  Megalocyte. 

4.  5,  6,^7,  8,  9,  ID,  II,  12,  13.    Poikilocytes.     Many  of  these  cells  are  highly  polychromato- 

philic,  especially  11,  12,  and  13. 

{Eosin  and  Methylene-blue.) 

Fig.  5.     Erythrocytes  Showing  Degenerative  Stroma  Changes. 

Granular  basophilia  is  shown  by  i  and  2  ;  extreme  decolonization  by  3,  4,  and  5.    The  other 
cells  represent  various  stages  of  hemoglobin  loss  and  protoplasmic  degeneration. 


Fig.  1. 


.«■*-• 


m 


Plate  I. 


m 


jtat. 


lO 


Fig.  3. 


1  V. 


o 


12 

m 


13 


10 


11 


H^^^- 


FiG.  2. 


13 


10 


Fig.  4. 


11 


12 


Fig.  5. 

The  Erythrocytes. 

(Figs.  I,  2,  3,  and  4,  Triacid  Stain ;  Fig.  5,  jEojzn  and  Methylene-blue.) 

(E.  F.  FABER,y>c.) 


SECTION   III. 

HEMOGLOBIN,  ERYTHROCYTES,  BLOOD   PLAQUES, 

AND    HEMOCONIA. 


I.    HEMOGLOBIN. 


Hemoglobin^  which  occurs  in  the  circulating 
General       blood  in  chemical  union  with  oxygen  as  oxyhem- 

Properties.  oglobin,  is  an  extremely  complex  ferruginous  and 
albuminoid  substance  contained  within  the  stroma 
of  the  erythrocytes.  It  constitutes  approximately  nine-tenths  of 
the  latter' s  total  bulk,  and  a  trifle  less  than  fourteen  per  cent,  of 
the  whole  blood.  Hemoglobin  displays  a  striking  avidity  for 
combining  with  oxygen  to  form  a  peculiarly  unstable,  but  defi- 
nite, chemical  compound,  and  a  similar  facility  for  yielding  up  to 
the  tissues  much  of  its  oxygen,  during  its  passage  through  the 
capillary  circulation.  Under  the  influence  of  deoxidizing  agents, 
oxyhemoglobin  may  be  deprived  of  its  loosely  combined  oxygen 
molecule,  the  resulting  oxygen-free  constituent  being  known  as 
reduced  hemoglobin.  Rhombic  crystals  of  oxyhemoglobin,  scarlet 
or  reddish-green  in  color,  are  rapidly  formed  if,  for  any  reason, 
separation  of  this  substance  from  the  corpuscular  stroma  takes 
place.  Methemoglobin  is  an  oxygen  compound  of  hemoglobin 
containing  the  same  quantity  of  combined  oxygen  as  the  latter, 
but  differing  from  it  in  holding  its  oxygen  constituent  in  a  more 
intimate  union.  The  dingy  brown  color  which  develops  in  a  so- 
lution of  oxyhemoglobin  after  prolonged  exposure  to  the  atmos- 
phere, evidences  the  production  of  this  variety  of  blood-pigment. 
(See  **  Methemoglobinemia,"  page  124.) 

The  amount  of  iron  (in  the  form  of  hemochromogeri)  which 
hemoglobin  contains  is  considerable — somewhat  in  excess  of 
four  per  cent.  It  has  been  shown,  clinically,  by  estimates  made 
with  the  ferrometer  and  the  hemometer,  that  no  fixed  parallelism 
is  maintained  between  the  percentage  of  hemoglobin  and  the  iron 
contained  in  the  blood.  ^ 

Under  the  action  of  acids,  strong  alkalies,  or  heat,  hemoglobin 
may  be  readily  decomposed  into  two  constituents  :  hematin,  or 
an  iron-containing  principle  ;  and  an  albuminous  residue  of  un- 
known character,  but  somewhat  resembling  globulin.     In  combi- 

1  Rosin  and  Jellinek  :  Zeitschr.  f.  klin.  Med.,  1900,  vol.  xxxix.,  p.  109. 


I20  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONL\. 

nation  with  hydrochloric  acid  hematin  forms  a  crj-stalHne  hydro- 
chloride of  hematin.  termed  hcinin,  or  Tcichmann  s  crystals. 
Under  the  microscope  these  crystals  appear  as  black  or  dark 
brown,  elongated  rhombic  prisms  belonging  to  the  triclinic  sys- 
tem, which  are  insoluble  in  water,  alcohol,  ether,  chloroform, 
and  dilute  acids.  They  may  be  demonstrated  by  preparing  a 
slide  of  blood  (or  of  any  dried  substance  containing  blood-pig- 
ment) to  which  a  small  quantit}^  of  common  salt  has  been  added; 
a  drop  of  glacial  acetic  acid  is  then  run  beneath  the  cover-glass 
so  that  it  mixes  with  the  blood  and  salt,  and  the  specimen  thus 
prepared  is  heated  to  just  below  the  boiling  point  over  a  Bunsen 
flame.  On  cooling,  Teichmann's  cry^stals  may  be  seen  under  the 
microscope  with  a  low-power  dry  objective. 

Iron-free  hematin,  or  hcmatoporpliyrin,  may  be  derived  from 
blood  by  the  admixture  of  concentrated  sulphuric  acid.  This 
substance  is  closely  related  chemically  to  urobilin,  and  occurs  oc- 
casionally as  a  pigment  in  nature  and  in  normal  and  pathological 
urines.  Hematoidin,  which  also  is  free  from  iron,  occurs  in  the 
form  of  reddish  rhombohedral  cr}-stals,  only  in  old  clots  resulting 
from  blood  extravasations,  such  as  cerebral  hemorrhages,  and 
splenic  infarcts.  It  is  derived  from  hematin,  and  is  probably 
identical  with  bilirubin. 

The  chief  source  of  hemoglobin  is  the  iron 
Origin.  contained  in  various  food  products,  about  ten 
milligrammes  daily  representing  the  amount  of 
this  metal  ingested  in  an  ordinar}'  diet,  according  to  the  analyses 
of  Stockman.^  In  event  of  a  stoppage  of  this  source  of  an  iron 
supply,  the  formation  of  hemoglobin  may  proceed  from  the 
supply  of  iron  stored  up  in  various  organs  of  the  body,  notably 
in  the  liver.  Bunge-  has  shown  that  in  the  young  infant,  whose 
natural  food,  milk,  contains  but  a  slight  trace  of  iron,  this  source 
of  hemoglobin  manufacture  is  most  potent. 

The  recent  experiments  of  Aporti^  regarding  the  origin  of 
hemoglobin  and  the  er}throcytes  have  shown  that  animals  sub- 
jected to  repeated  bleedings  and  kept  on  an  iron-free  diet,  are  able 
up  to  a  certain  point  to  utilize  the  supply  of  body  iron  for  hemo- 
globin manufacture  ;  but  that  when  such  a  demand  became  so 
severe  that  this  supply  was  exhausted,  the  red  corpuscles  became 
progressively  paler  and  paler,  and  the  animal  finally  died.  During 
the  course  of  these  experiments,  if  the  animal  received  injections 
of  iron,  a  prompt  and  striking  increase  in  hemoglobin  occurred, 

ijourn.  of  Physiol.,  1897,  vol.  xxi.,  p.  55  ;    1895,  vol.  xviii.,  p.  484. 
^Zeitschr.  f.  physiol.  Giem.,  1892,  vol.  xvi.,p.  177. 
^Centralbl.  f.  inn.  Med.,  1900,  vol.  xxi.,  p.  41. 


HEMOGLOBIN.  12  1 

the  gain  ranging  from  50  to  95  per  cent,  within  a  week's  time. 
The  injection  of  arsenic,  on  the  contrary,  produced  no  effect  upon 
the  hemoglobin  percentage,  although  it  caused  a  marked  and  rapid 
increase  in  the  number  of  red  corpuscles.  Similar  effects  from 
the  administration  of  these  drugs  in  the  treatment  of  the  different 
anemias  may  be  observed  as  everyday  clinical  occurrences. 

Diminution  in  the  amount  of  hemoglobin,  as 
Variations  indicated  by  the  hemometer,  is  known  as  oligo- 
IN  Amount,  chroineniia,  or  achroiocythemia.  It  is  a  condition 
usually,  but  not  invariably,  associated  with  a  cor- 
responding decrease  in  the  number  of  erythrocytes.  An  ap- 
parent increase  in  the  hemoglobin  percentage  may  result  from  the 
concentration  of  the  blood  caused  by  a  reduction  in  the  quantity 
of  blood  plasma  consequent  to  excessive  drains  upon  the  liquids 
of  the  body.  By  a  similar  physical  mechanism,  factors  pro- 
ducing a  dilution  of  the  blood  are  capable  of  causing  an  ap- 
parent diminution  in  the  hemoglobin.  Marked  oligochromemia 
is  commonly  observed  in  chlorosis,  pernicious  anemia,  and 
leukemia ;  and  in  the  secondary  anemias  dependent  upon  such 
factors  as  hemorrhage,  mineral  poisoning,  acute  and  chronic  in- 
fections, malignant  neoplasms,  and  constitutional  diseases.  The 
behavior  of  the  hemoglobin  under  such  conditions  is  more  fully 
alluded  to  in  connection  with  the  lesions  in  question.  Poggi,^  from 
a  series  of  experiments  upon  normal  women,  has  shown  that  the 
hemoglobin  is  slightly  lowered  (10  or  15  per  cent.)  for  a  few  days 
before  menstruation,  but  with  the  establishment  of  the  flow  the 
oHgochromemia  soon  disappears.  The  primary  loss  he  attributes 
to  retarded  hemogenesis  consequent  to  the  lessened  consumption 
of  albumin  occurring  in  menstruating  women,  while  the  subse- 
quent gain  he  explains  by  the  increased  functional  activity  of  the 
hematopoietic  organs. 

In  passing,  it  may  be  of  interest  to  compare  the  degree  of 
hemoglobin  loss  in  the  various  forms  of  anemia,  as  illustrated  by 
the  following  averages  determined  by  the  writer  : 

Average  of  50  estimates  in  pernicious  anemia 25.5  per  cent. 

''        ''     "  "         "  chlorosis 43.2     ''     '' 

"       "■     "■  "         "  leukemia 39.4     "     '' 

''        "     '^  "         "  secondary  anemia 55.2     ''     '' 

Bieifreund's  investigations  ^  in  Mickulicz's  clinic  have  led  to  the 
current  impression  among  surgeons  that  it  is  highly  dangerous  to 
give  a  general  anesthetic  to  a  patient  whose  hemoglobin  percent- 
age is  below  30  ;    some   operators   regard   40   per   cent,  as  the 

^Policlin.,  Roma,  1899,  vol.  vi,,  p.  i. 

2  Langenbeck's  Archiv. ,  1890-91,  vol.  xli.,  p.  i. 


122  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

lowest  limit  of  safety,  and  refuse  to  employ  any  but  a  local  anes- 
thetic in  cases  with  an  oligochromemia  exceeding  this  figure,  ex- 
cept  under  circumstances   of   imperative    necessity.     Any   one, 
however,  who  has  attempted  to  verify  the  correctness  of  this  gen- 
eral belief  must  accept  it  with   a  shrug  of  the  shoulders.     The 
writer  knows  of  four  patients  whose  hemoglobin  percentages  all 
were  below  30,  in  whom  operations  under  general  anesthesia  with 
ether  were  followed  by  uneventful  recovery ;  in  one  instance  (a 
pan-hysterectomy,  lasting  more   than  an  hour  and  a  half),  the 
hemoglobin  was  but  21  per  cent.,  yet  no  ill  effects  were  observed. 
Assuming  that  in  the  normal  adult  14  grammes 
Absolute      represent  the  average  amount  of  hemoglobin  in 
Amount.       100  grammes  of  blood,  the  absolute  amount  of 
hemoglobin  may  be  readily  calculated,  thus  : 

,._         ,  ,.  ^  Graimnes    of  hemog'lobiti 

HejnoHooin   percentao;e  x   14  -r-  100  =  •      __  -^  r  ui    j 

*  ^  ^  ^  in  100  grammes  of  oLooa. 

For  example,  in  blood  in  which  the  percentage  of  hemoglobin, 
as  determined  by  the  hemometer,  is  found  to  be  40,  the  calcula- 
tion (40  X  .14)  gives  the  absolute  amount  of  hemoglobin  as  5.6 
grammes. 

The  proportionate  amount  of  hemoglobin  con- 

CoLOR         tained    in  each  red  blood  corpuscle,  or  its  cor- 

Index.         puscular  richness  in  hemoglobin,  is  known  as  the 

coloi'  index,  or  blood  quotient,  or  valeiir  globidaire. 

In  normal  blood  the  color  index  is  theoretically  expressed  by  the 

figure  I,  although,  practically,  it  varies  from  .95  to  1.05  in  men, 

and  from  .9  to  i  in  women. ^ 

In  those  anemias  in  which  the  decrease  in  the  amount  01 
hemoglobin  in  the  blood  is  coincident  with  a  proportionate  de- 
crease in  the  number  of  erythrocytes,  the  color  index  remains 
practically  at  the  normal  figure.  If,  however,  the  cellular  de- 
crease happens  to  be  relativ^ely  greater  than  the  hemoglobin 
loss,  then  the  index  will  naturally  be  found  to  rise  above  normal ; 
thus,  in  pernicious  anemia,  in  which  condition  the  loss  of  cells 
is  proportionately  much  greater  than  the  loss  of  hemoglobin, 
high  color  indices,  approaching  or  even  exceeding  1.25,  are  fre- 
quently observed.  On  the  contrar>',  \i  the  hemoglobin  loss  is  rela- 
tively more  excessive  than  the  corpuscular  decrease,  the  color 
index  falls  below  normal ;  for  example,  in  chlorosis,  in  which,  as 
a  rule,  the  decrease  affects  the  hemoglobin  much  more  strikingly 
than  the  erythrocytes,  low  indices,  such  as  .50  or  less  are  common. 

To  calculate  the  color  index,  the  percentage  of  hemoglobin  is 

1  Oliver  :   Loc.  cit. 


HEMOGLOBIN.  1 23 

divided  by  the  percentage  of  eiythrocytes,  the  result  being  ex- 
pressed in  decimals.  In  order  to  simplify  this  procedure,  5,000,- 
000  erythrocytes  per  cubic  millimeter  must  be  arbitrarily  con- 
sidered as  normal,  or  100  per  cent.  To  obtain  the  percentage  of 
corpuscles,  the  actual  number  counted  in  one  cubic  millimeter  of 
blood  is  simply  multiplied  by  two,  and  two  or  three  decimals 
pointed  off  from  the  left,  depending  upon  whether  the  count  is 
below  or  above  the  normal  5,000,000.  The  following  examples 
serve  to  illustrate  the  calculation  in  several  conditions  : 
Normal  Adult. 

Erythrocytes  :   5,000,000  per  cb.  mm.  (100  per  cent.). 

Hemoglobin  :   100  per  cent. 

100  -i-  100  =  I  :   Color  index. 
Secondary  Aiiernia. 

Erythrocytes  :  2,650,000  per  cb.  mm.  (53  percent). 

Hemoglobin  :  40  per  cent. 

40  -J-  53  =  .75  :  Color  index. 
Per7iicious  A7ie7nia. 

Erythrocytes  :  840,000  per  cb.  mm.  (16.8  per  cent.). 

Hemoglobin  :   1 8  per  cent. 

18  -f-  16.8  =  1.07  :  Color  index. 
Chlorosis. 

Erythrocytes  :  4,100,000  per  cb.  mm.  (82  per  cent.). 

Hemoglobin  :   32  per  cent. 

32-5-82  =.39:  Color  index. 

These  examples,  of  course,  refer  only  to  the  usual  blood-find- 
ings, for  the  color  index  is  by  no  means  akvays  high  in  pernicious 
anemia,  nor  always  low  in  chlorosis.  The  color  index  shows 
simply  the  relative  relations  of  the  hemoglobin  and  the  corpus- 
cular percentages.  It  is  only  suggestive,  not  diagnostic  of  a 
specific  blood  disease. 

The  term  hemoglobinemia  is  used  to  designate 

Hemoglo-      a  condition  in  which  the  hemoglobin  is  dissolved 

BiNEMiA.        from   the   corpuscular   stroma,  as   the   result   of 

some  pathological  factor,  and  is  held  in  solution 

by   the   blood  plasma.     In   extreme   instances   this   condition  is 

sooner  or  later  succeeded  by  hemoglobinuria. 

Among  the  most  potent  causal  factors  of  hemoglobinemia  are 
certain  drugs  which  act  as  blood-poisons,  when  administered  in 
toxic  doses,  of  which  the  following  are  examples :  arseniuretted 
hydrogen,  sidpJmretted  hydrogen,  potassium  chlorate,  carbolic  acid, 
hydrochloric  acid,  sulphuric  acid,  pyrogallic  acid,  ?iitrobenzol,  anti- 
mo7iy  sulphide,  iodine,  naphthol,  and  many  of  the  coal-tar  deriva- 
tives, such   as   acetanilid,  antipyrin,  and  phenacetin.     A   similar 


124  ERYTHROCYTES,     BLOOD    PLAQUES,  AND    HEMOCONIA. 

liberation  of  the  hemoglobin  may  be  observed  as  the  result  of 
poisoning  by  certain  varieties  of  viusJirooms,  by  some  s?iake- 
ve7ioins,  by  the  bite  of  scorpions,  and  by  a  number  of  vegetable 
glycosides.  Sunsti'oke,  exteiisive  burns,  and  exposure  to  excessive 
cold,  are  also  capable  of  giving  rise  to  hemoglobinemia.  Experi- 
mentally, hemoglobinemia  may  be  produced  by  the  transfusion 
of  blood  from  one  animal  into  the  circulation  of  another  belonging 
to  a  different  species. 

Hemoglobinemia  is  observed  with  more  or  less  constancy  in  a 
number  of  acute  infectious  diseases  such  as  grave  cases  of  septice- 
mia, diphtheria,  malignant  jaimdice,  syphilis,  malarial  fever,  enteric 
fever,  scarlet  fever,  yellozu  fever,  typhus  fever,  and  variola.  It  also 
may  occur  in  scurvy,  and  in  Raynatid's  disease,  and  is  a  prominent 
blood-finding  in  those  two  obscure  conditions  known  as  epidemic 
hemoglobinuria  of  the  new-born,  and  paroxysmal  hemoglobinuria. 

Hemoglobinemia  may  be  readily  detected  by  the  following 
method,  recommended  by  von  Jaksch:^ — A  small  amount  of 
blood,  drawn  from  the  patient  by  means  of  a  cupping-glass,  is 
immediately  placed  in  a  refrigerator,  in  which  it  is  allowed  to  re- 
main for  twenty-four  hours.  In  normal  blood,  the  serum  which 
separates  at  the  expiration  of  this  period,  is  of  a  perfectly  clear 
straw-color,  whereas  if  hemoglobinemia  exists  the  serum  is  colored 
a  beautiful  ruby-red.  If  this  hemoglobinemic  serum  is  examined 
with  the  spectroscope,  the  two  characteristic  absorption  bands  of 
oxyhemoglobin  may  be  observed.  If  it  is  coagulated  by  heat,  a 
deep  brown  color  is  imparted  to  the  coagulum. 

Methemoglobinemia,    or    the    presence   in    the 
Methemoglo-  circulating   erythrocytes    of    methemoglobin,    is 
BiNEMiA.       produced   by  the    action  of   a  number  of  toxic 
substances,  which,  if  given  in  sufficiently  massive 
doses,  may  seriously  or  fatally  cripple  the  oxygenating  functions 
of  the  blood.     Among  the  agencies  which  cause  this  conversion 
of  oxyhemoglobin  into  methemoglobin  are  potassium  chlorate, 
aniline,  iodine,  bromine,  ether,  turpentine,  acetaiiilid,  potassiiim  per- 
manganate, hydrochinon,  kairin,  thallin,  and  pyrocatechin.     The 
inhalation  of  amyl  nitrite,  and  the  intravenous  injection  of  sodium 
nitrite  also  act  in  a  similar  manner. 

Spectroscopical  examination  of  the  blood  is  essential  for  the  de- 
tection of  methemoglobinemia.  The  spectrum  of  methemoglo- 
bin in  alkaline  solution  shows  three  absorption  bands  :  one 
well-marked  band  between  C  and  D  of  Fraunhofer's  lines  and 
two  others  of  much  less  distinct  appearance,  lying  between  D 
and  E,  each  immediately  adjacent  to  the  lines.      In  acid  and  neu- 

^  "Clinical  Diagnosis,"  etc.,  London,  1897,  3d  ed. 


HEMOGLOBIN. 


125 


tral  solutions  the  spectrum  of  methemoglobin  shows  four  absorp- 
tion bands  :  a  decided  one  between  C  and  D,  two  between  D  and 
E,  and  one  closely  adjacent  to  F.  This  spectrum,  it  is  true,  is 
identical  with  that  produced  by  an  acid  solution  of  hematin,  but 
it  may  be  easily  distinguished  from  the  latter  by  the  fact  that 
the  spectrum  of  methemoglobin,  when  acted  upon  by  ammonium 


Fig. 


c 


D 


5    b 


Oxyhemoglobin 


Methemoglobin 


Reduced  Hemoglo- 
bin 


C  0  Hemoglobin 


Principal  blood  spectra. 


sulphide,  changes  first  to  that  of  oxyhemoglobin,  and  later  to 

that  of  reduced  hemoglobin,  while  when  hematin  is  thus  treated, 

a  spectrum  which  shows  two  bands  between  D  and  E  is  produced. 

Aside  from  the  bright,  cherry-red  color  of  the 

Carbon  Mon-  blood  in  coal-gas  poisoning,  the  presence  of  car- 

oxiDE  Hemo-  bon  monoxide  hemoglobin  may  be  determined  by 

globin.        spectroscopical  examination,  and  by  a  number  of 

distinctive  chemical  reactions. 

Recalling  the  characteristic  spectrum  of  oxyhemoglobin  ( two 

distinct  absorption  bands  between  D  and  E,  the  one  nearest  D 

being  darker,  narrower,  and  more  sharply  defined),  it  is  found  that 

in  the  spectrum  of  carbon  monoxide  hemoglobin  these  bands 

are  replaced  by  two  others,  also  between  D  and  E,  but  nearer 

together,  and  somewhat  closer  to  the  violet  end  of  the  spectrum. 

This  distinction,  which  may  be  so  slight  as  to  appear  confusing, 

is  at  once  emphasized  by  the  fact  that  the  addition  of  ammo- 


126  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

nium  sulphide  has  absolutely  no  effect  upon  the  carbon  monox- 
ide spectrum,  while  it  transforms  the  spectrum  of  oxyhemoglo- 
bin into  that  of  reduced  hemoglobin. 

Carbon  monoxide  hemoglobin  in  the  blood  is  also  demonstra- 
ble by  the  following  simple  test  devised  by  Hoppe-Seyler  :  ^ — A 
small  quantity  of  blood,  removed  from  the  patient  by  means  of 
a  wet-cup,  is  mixed  with  twice  its  volume  of  a  ten  per  cent,  solu- 
tion of  potassium  hydrate.  Thus  treated,  blood  containing  car- 
bon monoxide  hemoglobin  changes  the  color  of  the  mixture  to  a 
rich,  cinnabar-red,  while  with  normal  blood  the  solution  turns 
brownish-green. 

II.     THE  ERYTHROCYTES. 

The  crytJivocytcs  or  red   corpuscles    are    thin, 
Appearance    flattened,    biconcave    discs,    of    sharply-defined, 
IN  regular  outline,  and  of  smooth,  even  surface.     In 

Fresh  Blood,  the  blood  of  the  normal  individual  they  do  not 
possess  a  nucleus.  When  the  corpuscle  is  ex- 
amined microscopically  as  it  rests  upon  its  flat  surface,  its  cen- 
tral concavity  is  plainly  indicated  by  a  dark,  central  area  sur- 
rounded by  a  narrower,  lighter  rim,  a^  the  periphery  of  the  cell 
is  brought  into  sharp  focus  ;  changing  to  a  pale,  white  center 
encircled  by  a  darker  periphery,  as  the  objective  is  brought  closer 
to  the  corpuscle.  When  viewed  in  profile  the  corpuscle  is  shaped 
somewhat  like  a  slim  dumb-bell,  with  regularly  rounded  poles 
tapering  from  either  end  toward  a  shallow  central  concavity  on 
either  surface.  Their  color,  when  examined  singly  under  the 
microscope,  is  a  pale  greenish-yellow,  but  when  collected  to- 
gether in  masses  a  more  or  less  marked  reddish  tint  becomes  ap- 
parent.- The  erythrocytes  possess  a  peculiar  tendency  of  collect- 
ing and  adhering  together  in  more  or  less  regularly  arranged 
piles,  like  rolls  of  coins  stacked  up  face  to  face,  this  being  known 
as  rouleaux  formation. 

After  withdrawal  of  the  blood  from  the  body  various  structural 
changes  in  the  erythrocytes,  commonly  known  as  creuation,  may 
be  observed.  In  normal  blood,  the  rapidity  with  which  these 
changes  progress  depends  upon  the  quantity  of  air  which  leaks 
in  between  the  slide  and  the  cover-glass,  and  thus  causes  de- 
generation of  the  corpuscular  stroma.  The  development  of  one 
or  more  small,  bright,  highly-refractive  spots  in  the  body  of  the 
corpuscle,  or  a  slight  indentation  of  the  cell's  peripher)^  are  the 
most  conspicuous  indications  of  beginning  crenation.  As  the 
process  goes  on,  more  and  more  of  these  hyaline  points  develop, 

^  Loc.  cit. 


THE     ERYTHROCYTES.  12/ 

until  finally  the  whole  surface  of  the  corpuscle  becomes  thickly 
studded  with  glistening,  bead-like  spines.  As  the  stroma  be- 
comes drier  and  drier,  its  typical  biconcavity  and  sharply-cut  out- 
line are  lost,  contracting  strands  of  the  stroma  are  seen  to  extend 
from  point  to  point  among  the  beaded  projections,  the  periphery 
of  the  cell  changes  to  a  cogged  rim,  and  finally  the  cell  becomes 
shrunken  and  shrivelled  up  into  a  small,  many-starred  asterisk. 
Some  of  the  erythrocytes  become  fragmented,  and  small  bits  of 
their  stroma  are  observed  to  break  off  and  float  through  the 
plasma.  Others  become  progressively  paler  and  paler,  as  the 
hemoglobin  is  dissolved  out,  until  complete  decoloration  occurs. 
Still  others  become  distorted  into  designs  of  every  conceivable 
shape,  so  that  their  resemblance  to  the  normal  cell  becomes  most 
remote.  These  changes,  which  never  occur  in  normal  blood 
until  the  cells  have  been  exposed  to  prolonged  atmospheric  in- 
fluence, must  not  be  confused  with  similar  alterations  in  the 
structure  of  the  erythrocytes  occurring  as  the  result  of  patholog- 
ical states  of  the  blood.  The  latter  changes  are  described  more 
fully  in  another  place.     (See  page  141.) 

The  finer  structure  of  the  erythrocyte  is  still  a 
Histological  mooted  point  among  different  histologists,  the 
Structure,     view  most  generally  accepted  regarding  it  as  a 
homogeneous    cell    composed    of    an    insoluble 
spongy  network,  the  stroma  of  Rollet,  in  the  interstices  or  trabec- 
ulae  of  which  is  embedded  a  soluble,  finely  granular  substance, 
the  hemoglobin,  existing  probably  as  a  compound  with  some  un- 
known   constituent    of  the  cell.     In   lieu  of  a  distinct  limiting 
membrane,  the  portions  of  the  stroma  nearest  to  the  surface  of 
the  corpuscle  are  condensed,  to  protect  it  from  injury  during  its 
movements  through  the  blood  stream.    The  corpuscles  are  highly 
elastic  and  contractile,  to  permit  of  the  rapid  and  marked  tempo- 
rary distortions  of  shape  which  they  constantly  undergo  in  the 
circulating  blood. 

Other  authorities,  notably  Schaffer,^  disagree  with  this  view, 
inclining  ratlier  toward  the  opinion  advocated  by  the  earlier  in- 
vestigators, who  considered  the  erythrocytes  as  vesicular  masses, 
consisting  of  an  external  envelope  enclosing  a  fluid  contents. 
Thus,  Schaffer  beheves  that  the  cell  consists  of  two  distinct  por- 
tions, a  colored  and  a  colorless,  the  former  being  a  solution  of 
hemoglobin,  while  the  latter,  or  so-called  stroma,  consists  chiefly 
of  lecithin  and  cholesterin,  together  with  a  small  amount  of  cell 
globulin.  Without  attempting  to  discuss  the  correctness  of  either 
of  these  two  views,  a  single  tangible  reason  for  regarding  the  cor- 

iQuain's  "Anatomy,"  Phila.,  1891,  pt.  2,  p.  210. 


128  ERYTHROCYTES,    BLOOD    PLAQUES,    AND    HEMOCONIA. 

puscle  according  to  Rollet's  opinion  may  be  stated,  viz  :  the  fact 
that  exposure  of  blood  to  destructive  temperatures  results  in 
fragmentation  of  the  corpuscles  into  numerous  minute  portions, 
each  one  of  which  consists  of  a  bit  of  hemoglobin-containing 
stroma.  This  obviously  seems  to  disprove  the  existence  of  a 
limiting  membrane,  without  further  investigation. 

In  the  human  body  an  active  manufacture 
Origin  and  of  red  corpuscles  constantly  goes  on  during 
Life  History,  health,  in  order  to  compensate  for  the  continuous 
drain  on  their  number  by  the  destruction  of  those 
cells  which  have  become  incapable  of  function  and  useless,  their 
life  cycle  being  run.  That  this  reproduction  is  the  direct  answer 
to  a  call  for  new  cells  is  proved  by  the  prompt  and  rapid  increase 
of  corpuscles  following  the  loss  of  blood  from  hemorrhage  ;  that 
such  a  manufacture  is  attempted  in  severe  pathological  conditions, 
although  the  attempts  are  sometimes  abortive,  is  evinced  by  the 
large  numbers  of  immature  and  misshapen  erythrocytes  which 
appear  in  the  blood  in  certain  of  the  grave  anemias. 

In  the  adult  it  is  generally  conceded  that  the  erythrocytes 
are  reproduced  in  the  red  bone  marrow,  being  developed  from 
their  direct  antecedents,  the  nucleated  erythroc\tes  or  erj'thro- 
blasts,  which  exist  in  this  tissue  in  large  numbers.  The  erj-thro- 
blasts  appear  to  multiply  in  the  thin-walled  capillaries  and  veins 
of  the  red  marrow,  and  having  lost  their  nuclei,  become  trans- 
formed into  normally  developed  erjthrocytes,  which  pass  from 
the  marrow  blood  channels  into  the  general  circulation.  Some 
authorities  have  attributed  to  the  spleen  and  lymphatic  glands  a 
share  in  the  formation  of  the  red  cells,  while  others  have  main- 
tained that  they  ma\'  be  transformed  from  the  leucocytes  in  the 
circulating-  blood,  but  none  of  these  theories  has  been  associated 
with  convincing  evidence,  so  that  it  is  fair  to  consider  the  red 
bone  marrow  the  chief,  if  not  the  only,  seat  of  production,  in 
the  light  of  our  present  knowledge  of  the  subject.  Hayem's 
ingenious  theor\',  that  the  red  corpuscles  arise  from  the  hema- 
toblasts,  does  not  enjoy  the  confidence  of  modern  investiga- 
tors. 

When  finally  the  er>throc>te,  after  having  executed  its  function 
for  a  certain  length  of  time,  becomes  useless  in  its  primaiy  office 
as  an  oxygen  carrier,  its  death  ensues,  the  destruction  of  the 
cell  probably  taking  place  largely  in  the  spleen,  whence  the 
freed  hemoglobin  is  carried  to  the  liver  to  be  eliminated  as  bile 
pigment.  Warthin's  *  recent  studies  apparently  show  that  de- 
struction  of  the  er}throcytes   also  occurs  in   the   splenolymph 

^  Jour.  Boston  Soc.  of  Med.  Sci.,  1901,  vol.  v.,  p.  414. 


THE     ERYTHROCYTES.  1 29 

glands,  minute  vascular  sinuses  situated  chiefly  in  the  retroperi- 
toneal and  mediastinal  tissues,  and  in  the  thyroid  and  thymus 
regions.  The  possibility  that  certain  of  the  partly  degenerate 
red  corpuscles  also  undergo  a  certain  form  of  repair,  first  in  the 
spleen  and  then  in  the  liver,  rendering  them  still  capable  of  func- 
tion, is  an  interesting  but  obviously  unproved  conjecture. 

The  average  diameter  of  the  erythrocyte  is  about 
Size.  7.5/-i,Mts  average  thickness  being  about  1.8//.  Ac- 
cording to  Gram,^  the  diameter  appears  to  vary  some- 
what with  the  geographical  and  climatic  conditions  surrounding 
the  individual,  being  considerably  larger  in  inhabitants  of  northern 
countries  than  in  southerners,  as  the  following  average  measure- 
ments of  this  observer  attest : 

Country.  Average  Diameter. 

Italy  7  to  7.5/a 

France 7.5  to  7.6/1 

Germany 7.8/i 

Norway 8. 5  /a 

Hayem  ^  distinguishes  three  different  sizes  :  large,  averaging 
8.5  /i  in  diameter;  medium,  averaging  7.5  //  in  diameter;  and 
small,  averaging  6.5  fi  in  diameter.  Of  these  three  classes,  ap- 
proximately 75  per  cent,  are  of  the  medium  size,  while  12.5  per 
cent,  each,  are  large  and  small.  The  diameter  varies  within  some- 
what wider  limits  in  the  infant  and  in  the  young  child  than  in  the 
adult.  It  is,  however,  not  materially  influenced  by  sex.  The 
pathological  increase  and  decrease  in  the  diameter  of  the  erythro- 
cytes occurring  in  certain  anemias,  are  discussed  in  another  place. 
The  normal  number  of  erythrocytes  in  the 
Normal  healthy  male  adult  may  be  approximated  at 
Number.  5,000,000  to  the  cubic  millimeter  of  blood. 
Higher  counts  than  this  are  frequently  observed, 
however,  especially  in  healthy,  well  developed  men,  so  that  this 
figure  should  be  taken  to  represent  a  rather  low  average,  subject 
to  an  upward  fluctuation  of  half-a-million  cells,  and  occasionally 
even  more.  In  females  a  count  of  about  4,500,000  red  cells  per 
cubic  millimeter  may  be  regarded  as  normal. 

Arterial  and  venous  blood  contain  practically  the  same  number 
of  corpuscles,  the  apparent  slight  increase  in  favor  of  the  latter, 
mentioned  by  some  observers,  being  within  the  limits  of  technical 
error.     For  a  like  reason,  under  normal  conditions,  peripheral 

1  The  Greek  letter  fi  is  used  to  represent  a  raicromillimeter,  or  l/r,ooo  of  a  milli- 
meter, which  is  a  standard  unit  of  measurement  used  in  microscopy. 
2Forschr.  d.  Med.,  1884,  vol.  ii.,  p.  2,3- 
3  Loc.  cit. 

9 


130         ERYTHROCYTES,    BLOOD    PLAQUES,  AND    HEMOCONIA. 

blood  may  be  taken  as  representative  of  the  blood  of  the  entire 
body.  Blood  derived  from  dependent  parts  of  the  body  contains 
a  diminished  proportion  of  corpuscular  elements.  Oliver's^ 
studies  of  this  question  have  shown  that  blood  from  the  finger 
invariably  gives  a  higher  count  of  red  cells  than  blood  from  the 
toe,  this  disparity  being  explained  by  the  fact  that  the  larger 
quantity  of  lymph  gravitating  to  the  more  dependent  parts  of  the 
body  causes  a  dilution  of  the  blood  in  these  areas. 

This  term  has  been  applied  by  Capps  ^  to  the 
Volume  figure  representing  the  percentage  volume  of  the 
Index.  individual  erj'throcyte,  in  contradistinction  to  the 
color  index,  which  expresses  the  amount  of  hemo- 
globin in  the  single  cell.  It  is  calculated  by  dividing  the  percent- 
age volume  of  the  erythrocytes  as  a  whole,  obtained  by  centrifu- 
galization  of  the  blood,  by  the  percentage  number  of  er}'throcytes, 
as  determined  by  the  actual  count  with  the  hemocytometer,  the 
normal  volume  index  being  taken  as  i.oo.  For  example,  the 
erjlhrocyte  column,  after  centrifugalization  with  the  hematocrit, 
reaches  to  the  mark  40  on  the  capillar)^  tube,  indicating  a  total 
volume  of  80  per  cent.;  while  the  count  with  the  hemocytometer 
gives  3,000,000  cells  per  cubic  millimeter,  or  60  per  cent,  of  the 
normal  number.  Then,  80  -r-  60,  or  1.33,  equals  the  volume  in- 
dex, a  figure  which  in  this  instance  shows  an  increase  of  33  per 
cent,  in  the  volume  of  each  corpuscle.  As  a  general  rule,  it  may 
be  stated  that  the  volume  index  and  the  color  index  rise  and 
fall  together,  although  the  parallelism  between  the  two  is  not  al- 
ways closely  maintained.  The  volume  index  is  generally  lowered 
in  chlorosis,  in  leukemia,  and  in  most  of  the  secondary  anemias, 
while  in  pernicious  anemia  it  tends  to  rise  above  the  normal 
standard. 

III.     INFLUENCE   OF   PHYSIOLOGICAL   FACTORS   ON 
THE    ERYTHROCYTES. 

Polycythemia,  associated  with  a  proportionately 
Age  AND  Sex.  high  percentage  of  hemoglobin,  is  found  in  the 
blood  of  the  new-born  infant  immediately  after 
birth,  the  maximum  counts  being  observed  some  time  during  the 
first  twenty-four  hours  of  life,  after  which  period  they  progres- 
sively diminish  until  at  the  end  of  about  eight  or  ten  days  an 
average  of  one  million  cells  has  been  lost.  Each  period  of  nursing 
is  generally  followed  by  a  prompt  temporar^^  decrease  in  the 
count,  and  a  similar  change  has  been  observed  as  the  effect  of 

1  Loc.  cit. 

2  Loc.  cit. 


INFLUENCE  OF  PHYSIOLOGICAL  FACTORS.  131 

premature  ligation  of  the  cord,  at  birth.  Hayem  ^  found  an  aver- 
age of  5,368,000  red  corpuscles  per  cubic  millimeter  in  17  infants 
at  birth,  the  highest  count  being  6,262,000,  and  the  lowest 
4,340,000.  The  cause  of  this  polycythemia  is  attributed  to  con- 
centration of  the  blood  from  the  abstraction  of  water  by  the  tissues 
to  replace  the  fluids  of  the  body  lost  during  the  first  few  days  of 
life.  As  soon  as  this  loss  is  made  up  by  the  ingestion  of  a 
sufficient  amount  of  liquids  by  the  child,  the  normal  relation  be- 
tween the  liquid  and  the  solid  portions  of  the  blood  is  reestab- 
lished, so  that  the  polycythemia  disappears. 

During  the  growth  of  the  adult  the  average  number  of  eryth- 
rocytes continues  to  rise,  until  the  maximum  number  is  attained 
at  some  time  between  the  third  and  fifth  decades,  after  which 
a  decrease  is  observed,  usually  becoming  more  marked  as  the 
decline  of  life  progresses.  Schwinge  ^  and  others  have  shown 
that  during  the  period  of  sexual  activity  the  counts  in  females  are 
generally  lower  than  in  males,  but  that  after  the  climacteric  the 
number  of  cells  in  the  two  sexes  is  practically  identical. 

The  influence  of  age  and  sex  upon  the  number  of  red  corpuscles 
is  well  illustrated  in  the  following  table  prepared  by  Sorensen  :  ^ 

Age.  Males.  Age.  Females. 

5  to  8  days..... 5,769,500  i  to  14  days 5,560,800 

5  years  4,950,000  2  to  20  years 5,120,000 

19.5  to  22  years 5,600,000         15  to  28  years 4,820,000 

25  to  30  years 5,340,000         41  to  61  years 5,010,000 

50  to  52  years 5,137,000 

82  years 4,174,700 

There  are  no  conspicuous  changes  in  the  num- 
Pregnancy,     ber  of  erythrocytes  in  any  of  these  conditions. 
Menstruation,  In  primiparae  there  is  often  a  slight  decrease  in 
AND  the   number  of  corpuscles,   particularly   in    the 

Lactation,  later  months  of  pregnancy,  but  in  multiparae 
this  change  is  rarely  observed.  During  men- 
struation there  may  be  a  trifling  reduction  caused  by  the  physi- 
ological hemorrhage  of  the  phenomenon,  but  the  loss  is  rapidly 
made  up  in  a  few  days'  time.  Sfameni  ^  found  that  a  transient 
polycythemia  usually  occurs  shortly  before  the  establishment  of 
the  menstrual  flow,  and  that  the  average  loss  of  hemoglobin  and 
corpuscles,  which  takes  place  in  the  majority  of  cases  during  the 

1  Loc.  cit. 

2Pfluger's  Archiv.,  1898,  vol.  Ixxiii.,  p.  299. 

3  Cited  by  von  Limbeck  :  "  Grundriss  einer  klinischn  Pathologie  des  Blutes," 
Jena,  1896. 

*Rassegna  di  ostetricia  e  ginecologia,  Jan.-Feb.,  1899.  Abstr.  in  Centralbl.  f. 
Gynakol.,  1899,  vol    xxiii.,  p.  1311. 


132  ERVTHROCVTES,    BLOOD    PLAQUES,    AND    HEMOCOXIA. 

flow,  does  not  exceed  4.5  per  cent.,  the  decrease  being  in  direct 
proportion  to  the  actual  volume  of  blood  lost. 

In  healthy,  robust  women  lactation  is  accompanied  by  a  normal 
count,  but  in  weak,  young  pregnant  girls,  particularly  those  of 
the  "  chlorotic  age,"  a  moderate  reduction  is  sometimes  observed. 
After  deliver}^  there  is  an  oligocythemia,  the  intensity  of  which 
depends  largely  upon  the  amount  of  blood  lost  and  upon  the 
general  health  of  the  woman  ;  this  loss  of  cells  is  gradually  made 
up,  and  unless  convalescence  is  delayed,  reaches  the  normal  by 
the  second  or  third  week  after  deliver>^ 

Well-developed,  robust  individuals  average  a 

Constitution  larger  percentage  of  red  cells  than  the  poorly- 

AND  nourished  and  weakly.      In   the  former,  counts 

Nutrition,     much  in  excess  of  five  million,  and  in  the  latter, 

counts  of  less  than  five  million,  are  the  rule. 
Fasting,  inasmuch  as  it  causes  a  drain  upon  the  liquid  elements 
of  the  intravascular  system,  may  rapidly  bring  about  an  apparent 
polycythemia  due  to  concentration  of  the  blood,  this  increase  in 
cells  being  in  direct  relation  to  the  length  of  abstinence  from  food. 
Hayem  ^  states  that  a  twenty-four  hours'  fast  will  cause  a  gain  of 
between  four  and  five  hundred  thousand  cells  ;  while  the  experi- 
ments of  Reyne  -  on  a  dog,  starved  to  death  after  a  twenty-four 
days'  fast,  showed  an  increase  of  2,500,000  corpuscles  at  the  ex- 
piration of  this  period. 

Physical  labor  prolonged  to  the  point  of  fatigue 
Fatigue.  appreciably  diminishes  the  number  of  er>-thro- 
cytes.  Cadet's^  investigations  of  the  blood  of  a 
number  of  peasants,  examined  after  two  months  of  hard  field 
labor  during  the  summer,  showed  a  moderate  oligocythemia — in 
one  instance  a  loss  of  over  one  million  cells,  and  in  the  others 
diminutions  averaging  about  one-half  of  this  figure.  Cadet  be- 
lieves that  this  anemia  is  referable  to  a  true  blood  destruction, 
and  notes  as  a  rather  mythical  support  of  this  view  that  the  blood 
plaques  were  increased  in  these  cases. 

Within  an  hour  or  two  after  a   meal  there  is 
Digestion,     a   slight,  transitory  increase   in   the   number   of 
Food.  erj'throcytes,  soon  followed  by  a  decrease  corre- 

sponding to  the  period  of  digestion  and  aver- 
aging a  loss  of  from  one  quarter  to  three  quarters  of  a  million 
cells.  The  preliminar)'  rise  has  been  attributed  to  abstrac- 
tion of  liquids  from   the   blood-vessels   consequent  to  the  pro- 

^  Loc.  cit. 

2  Cited  bv  Havem,  loc.  cit. 

3  Ibid. 


%. 


INFLUENCE    OF    PHYSIOLOGICAL   FACTORS.  1 33 

fuse  outpouring  of  the  gastric  secretions  ;  the  subsequent  fall 
depends  upon  temporary  dilution  of  the  blood  during  digestion, 
and  stands  in  inverse  ratio  to  the  leucocyte  count.  Oliver  ^ 
states  that  these  variations  are  not  affected  by  the  taking  of 
liquids  with  meals,  for  he  has  noticed  that  they  were  quite  as  pro- 
nounced when  water  was  withheld.  The  following  table,  from 
Von  Limbeck,^  illustrates  the  variations  in  the  red  and  white  cells 
caused  by  taking  food. 

Time.  Erythrocytes.  Leucocytes.      Hemoglobin. 

11:15  A.  M.  5.553.0CX)  7,666 
12  M.     Dinner  of  meat  and  farinaceous  food. 

12:15  P-  M.  5,320,000  6,166 

1:15  P.  M.  5,480,000  8,500 

2:15  P.  M.  4,733,000  12,000 

3:15  P.  M.  4,872,000  14,000 

4:15  P.  M.  4,720,000  10,830 

Hayem^  believes  that  meat  eaters  average  a  higher  percentage  of 

red  corpuscles  than  vegetarians,  on  account  of  the  more  nitrogenous 

character  of  their  food,  and  that  a  diet  of  fats  and  albuminoids  is 

most  favorable  for  the  increase  of  the  cellular  elements  of  the  blood. 

The  habitual  polycythemia  of  individuals  living 

High  in  high  altitudes  is  an  interesting  and  inadequately 

Altitudes,  explained  fact  in  hematology.  Viault,^  Wolff 
and  Koeppe,^  Egger^  and  other  observers  have 
shown  the  invariable  occurrence  of  this  polycythemia  both  in 
inhabitants  of  elevated  districts  and  in  the  occasional  visitor.  In 
the  case  of  the  latter,  as  the  individual  ascends  from  the  sea- 
level  to  the  mountainous  district,  a  rapid  increase  in  corpuscles 
and  in  hemoglobin  develops,  this  increase  bearing  a  certain  rela- 
tion to  the  height  ascended,  and  becoming  apparent  usually 
within  twenty-four  or  forty-eight  hours  after  his  arrival  in  the 
highland.  Viault  counted  8,000,000  erythrocytes  to  the  cubic 
millimeter  in  the  residents  on  the  Cordilleras,  at  an  elevation  of 
14,274  feet  above  the  sea-level;  Egger  counted  7,000,000  at 
Arosa,  at  a  height  of  6,100  feet;  and  Wolff  and  Koeppe  found  an 
average  of  5,970,000  in  dwellers  at  Reiboldsgriin,  at  a  height  of 
2,257  ^^^t.  Oliver^  relates  the  interesting  experience  of  finding  in 
his  own  blood,  during  a  stay  at  Davos  Platz,  at  an  elevation  of 
5,200  feet,  an  increase  of  corpuscles  within  twenty- four  hours  after 
his  arrival,  the  maximum  count,  5,550,000,  being  attained  within 
seven  days,  and  the  number  declining  within  five  days  after  his 

^  Loc.  cit. 

^Comptes  Rendus,  1890,  vol.  iii.,  p.  917. 
^Miinch.  raed.  Woch.,  1893,  vol.  xl.,  p.  904. 
*XII.  Congress  f.  Innere  Med.,  Weisbaden,  1893. 
5  Loc.  cit. 


134         ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

return  to  London.  The  hemoglobin  changes,  which  accompany 
these  corpuscular  alterations,  are  never  so  marked  as  the  latter, 
both  the  rise  and  the  fall  being  less  rapid  ;  consequently  it  is  com- 
mon to  find  a  low  color  index  at  first,  whereas,  later,  inasmuch 
as  the  rapidity  of  the  cellular  decrease  is  greater  than  the  fall  in 
hemoglobin,  a  high  color  index  is  apt  to  persist  for  some  time  after 
return  to  the  lowland. 

The  following  table  taken  from  Koeppe,^  illustrates  the  fact  that 
the  higher  the  altitude,  the  higher  is  the  count  of  erythrocytes  : 

Height  Above  Count  of 

Place.  Sea-level.  Erythrocytes.  Author. 

Christiania o  4,974,000  Laache. 

Gottingen 148  meters.  5,225,000  Schafer. 

Tubingen 314  "  5,322,000  Reinert. 

Zurich 414  ^'  5,752,000  Stierlin. 

Auerbach... 425  ^'  5,748,000  Koeppe. 

Reiboldsgriin 700  *'  5,900,000  Koeppe. 

Arosa 1,800  '^  7,000,000  Eggar. 

The  Cordilleras  ...4,392  "  8,000,000  Viault. 

Concentration  of  the  blood  doubtless  explains  the  polycythe- 
mia of  high  altitudes,  this  change  being  due  largely  to  the  great 
loss  of  body  fluids  (Grawitz),  and  partly  to  the  increased  arterial 
tension  (Oliver)  arising  from  a  rarefied  atmosphere.  Koeppe's 
ingenious  theory  that  the  process  mirrors  an  actual  manufacture 
of  new  cells  is  scarcely  tenable,  for  although  this  observer  has 
found  numerous  microcytes  and  poikilocytes  coincidentally  with 
the  appearance  of  the  polycythemia,  normoblasts  were  not  de- 
tected, as  an  evidence  of  rapid  hemogenesis,  nor  did  such  signs 
of  excessive  blood  destruction  as  icterus  and  hemoglobinuria  de- 
velop, as  the  increased  count  rapidly  declined,  on  the  individual's 
descent  to  a  lower  level. 

It  has  recently  been  urged  that  in  high  elevations  the  effect 
upon  the  hemocytometer  of  atmospheric  pressure  and  tempera- 
ture may  be  the  real  secret  of  the  cellular  increase,  but  how  such 
influences  act,  if,  indeed,  they  are  active,  is  unknown. 

IV.   PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES. 

True  ameboid  movements  of  the  erythrocytes 

Ameboid       are  sometimes  obser\^ed,  as  the  result  of  the  effect 

Motility.      of   globulicidal  agents,  or  of   some  pathological 

state  of  the  blood,  such  as  a  severe,  high-grade 

anemia.     The  inherent  elastic  and  contractile  qualities  shown  by 

the  cells,  by  virtue  of  which  they  undergo  various  changes  in 

1  Loc.  cit. 


PATHOLOGICAL    CHANGES    IN    THE    ERYTHROCYTES.  1 35 

shape  while  floating  about  in  the  plasma,  must  not  be  confounded 
with  the  actual  ameboid  motility  which  they  exhibit  in  disease. 
The  molecular  dancing  movements  of  bits  of  fragmented  corpus- 
cles, and  the  characteristic  motility  of  the  intracellular  hyaline 
malarial  parasite,  also  must  be  distinguished  from  the  progressive, 
deliberate  characteristics  of  the  truly  ameboid  red  blood  cell. 

Within   the   body  the  hemoglobin   and  other 

Alterations    constituents  of  the  erythrocytes   are  preserved 
IN  intact  within  the  corpuscular  stroma  by  the  com- 

IsoTONiciTY.  position  of  the  blood  plasma,  which  is  such  that 
a  perfect  osmotic  balance  is  constantly  main- 
tained. Outside  of  the  body,  if  this  relationship  is  disturbed  by  the 
addition  of  distilled  water  to  a  specimen  of  blood,  thus  lowering 
the  concentration  of  the  plasma,  a  rapid  discharge  of  hemoglobin 
from  the  corpuscle  into  the  surrounding  liquid  ensues,  but  the 
addition  of  saline  solutions  of  a  definite  strength  prevent  such  a 
change.  Solutions  of  salts  of  just  sufficient  concentration  to  pre- 
serve the  corpuscles  and  to  prevent  removal  of  their  elements 
are  known  as  isotonic ;  solutions  of  greater  strength  are  termed 
hypertonic^  and  those  of  lesser  strength  hypotonic.  In  normal 
blood  it  has  been  determined  that  the  isotonicity  of  the  eryth- 
rocyte usually  ranges  from  about  0.48  to  0.46  per  cent.  NaCl  ; 
that  is,  salt  solutions  of  this  concentration  are  just  sufficient  to 
prevent  the  discharge  of  hemoglobin  by  the  cell,  although  it  may 
swell  by  taking  up  water.  A  0.9  per  cent,  or  ''normal  "  salt 
solution  not  only  preserves  the  hemoglobin  within  the  cell,  but 
also  prevents  alterations  in  its  size  and  contour. 

Owing  to  the  conflicting  results  which  have  been  obtained  by 
different  investigators,  the  isotonicity  of  the  erythrocytes  in  differ- 
ent diseases  is  of  little  clinical  value.  Stengel  ^  found  the  per- 
centage 0.52  and  0.6  in  two  cases  oi  pernicious  anemia^  yet  in 
other  cases  the  figures  were  normal ;  in  other  diseases  marked  by 
anemia,  such  as  carcinoma,  hepatic  cirrhosis,  rental  disease,  and 
ttiberciilosis,  he  found  that  the  variations  were  trivial.  Von  Lim- 
beck ^  found  that  the  isotonicity  was  usually,  but  not  invariably, 
increased  in  high-grade  secondary  a7iemias,  in  leukemia,  and  in 
many  of  the  acute  infectio?is,  while  it  was  decreased  in  chlorosis, 
and  in  catarrhal  icterus.  A  decidedly  increased  isotonicity  was 
found  by  Vicarelli  ^  in  pregnant  and  nursing  women.  As  a 
general  rule,  it  is  believed  that  degenerative  changes  in  the  eryth- 
rocytes, whatever  their  nature,  predispose  to  dissociation  of  hem- 

^  Loc.  cit. 
2  Loc.  cit. 
"Cited  by  von  Limbeck,  loc.  cit. 


136  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

oglobin  from  the  stroma,  and  that  in  such  instances  the  isotonic 
percentages  are  higher  than  normal. 

In  the  fresh  specimen  of  blood,  exaggeration 

Hypervis-  of  the  adhesive  properties  of  the  er)lhrocytes 
cosiTY.  may  be  observed  in  a  number  of  conditions,  but 
up  to  the  present  time  no  special  clinical  signifi- 
cance has  been  assigned  to  the  phenomenon.  It  occurs  to  some 
extent  in  most  inflammator}^  diseases,  and,  according  to  Hayem,^ 
is  often  seen  in  the  anemias  associated  with  marked  cachexia. 
Striking  examples  of  hyper\iscosity  result  when  the  eiythrocytes 
are  subjected  to  the  action  of  various  poisons,  notably  snake 
ve7ioin,  and  of  heterogeneous  pathological  blood-serum.  From 
the  effect  of  such  influences  the  er3/i:hrocytes,  instead  of  forming 
normal  rouleaux,  tend  to  adhere  together  in  large,  irregular 
masses  in  which  the  distinctive  characteristics  of  the  cells  are 
masked  or  lost.  The  individual  cells,  unattached  to  such  a 
mass,  may  exhibit  every  possible  variety  of  distortion,  losing 
their  typical  biconcavity  and  regular  disc-like  appearance,  and 
becoming  converted  into  elongated,  misshapen  bodies.  It  fre- 
quently happens  that  the  cell  is  provided  with  one  or  more 
long,  delicate  processes  several  times  the  length  of  its  diameter, 
this  being  due  to  the  adhesion  of  a  bit  of  the  stroma  to  the  cover- 
glass  while  preparing  the  specimen  ;  in  the  spread  film  it  will  be 
noted  that  these  processes  all  point  in  the  same  direction. 

Changes  in  the  shape  and  size  of  the  eryth- 

Deformities   rocytes  are  common  in  all  anemias  which  reach 

OF  a   severe    grade,  the  degree  of  such  deformities 

Shape  and     corresponding    closely    to    the   intensity  of    the 

Size.  anemic  process.     The  diameter  of  the  cells  may 

be  more  or  less  uniformly  increased  or  decreased, 

and  such  pronounced  alterations  in   their  shape  may  occur  that 

many  of  them  bear  but  slight  resemblance  to  the  typical  disc's  of 

normal  blood.     (Plate  I.) 

When  the  corpuscle  becomes  greatly  enlarged  in  diameter  it  is 
known  as  a  niegalocyte  or  inacrocyte,  the  presence  of  large  num- 
bers of  such  cells  being  known  as  nicgalocytosis  or  niacrocytosis. 
The  diameter  of  a  megalocyte  generally  varies  from  9  to  1 2  /i, 
but  sometimes  much  larger  forms  are  seen,  measuring  as  much  as 
20  }i.  They  are  present  in  the  severer  anemias,  especially  in  the 
pernicious  form,  in  which  they  constantly  occur  in  large  numbers. 
The  megalocyte  found  in  this  disease  is  usually  characterized  by 
an  excess  of  hemoglobin,  while  in  the  secondary  anemias  such 
cells  are  generally  deficient  in  their  hemoglobin  content. 

1  Loc.  cit. 


PATHOLOGICAL    CHANGES    IN    THE    ERYTHROCYTES.  1 3/ 

The  smaller  forms,  the  microcytes,  illustrate  the  extreme  de- 
crease in  size  of  the  red  cell  under  pathological  conditions.  The 
microcyte  is  an  extremely  small  globular  body,  measuring  from 
about  3  to  5  /i  in  diameter.  It  is  found  in  all  the  varieties  of 
anemia,  but  is  most  commonly  associated  with  chlorosis,  and  with 
the  moderately  developed  secondary  forms.  When  abundantly 
found  in  the  blood,  the  condition  is  known  as  microcytosis. 

Eichhorsf  s  corpuscles  are  deeply  colored,  highly-refractive  mi- 
crocytes,  about  3  a  in  diameter,  and  usually  of  regularly  spherical 
shape.  They  were  once  regarded  as  pathognomonic  of  pernicious 
anemia,  but  are  now  considered  diagnostic  of  no  especial  condi- 
tion, being  frequently  found  in  severe  anemias  of  any  type,  and 
often  being  absent  in  pernicious  anemia. 

It  seems  reasonable  to  infer  that  deformities  in  the  size  of  the 
erythrocyte  are  referable  chiefly  to  two  different  factors  :  to  faulty 
hemogenesis,  and  to  degenerative  changes  of  the  corpuscle  which 
lead  to  alterations  in  its  histological  structure.  Megalocytes,  for 
example,  may  in  some  instances  represent  an  actual  giantism  of 
the  cell,  bred  in  the  marrow  from  correspondingly  large-sized 
nucleated  antecedents  ;  in  other  instances  (of  which  those  exceed- 
ingly pale,  ''washed  out"  forms  are  examples)  their  abnormal 
size  may  be  attributed  to  hydropic  enlargement,  resulting  from 
their  imbibition  of  fluids  from  the  surrounding  plasma.  Micro- 
cytes  may  enter  the  circulating  blood  as  such,  or,  as  is  frequently 
the  case,  they  may  be  the  products  of  corpuscular  budding  and 
fragmentation. 

In  severe  forms  of  anemia,  characterized  by  excessive  cellular 
loss,  there  appears  also  to  be  a  tendency  toward  a  compensatory 
hypertrophy  of  many  of  the  erythrocytes,  in  order  thus  to  in- 
crease the  oxygen- car  lying  capacity  of  the  blood,  which,  were  it 
not  for  these  numerous  megalocytes,  might  in  some  instances  be 
too  limited  to  sustain  life. 

Poikilocytcs  are  erythrocytes  deformed  in  shape  as  the  result 
of  some  pathological  condition  of  the  blood.  Poikilocytosis,  the 
name  by  which  this  condition  is  designated,  is  akin  to  crenation 
in  so  far  as  in  both  conditions  the  cells  may  be  similarly  distorted 
and  misshapen.  But  it  is  unlike  crenation  for  the  reason  that 
poikilocytosis  is  a  pathological  condition,  and  demonstrable  the 
moment  the  blood  is  withdrawn  from  the  body  ;  while  crenation 
is  a  physiological  phenomenon  depending  upon  external  influences 
for  its  production,  and  never  occurring  until  the  blood  has  re- 
mained exposed  to  the  air  for  some  time.  Poikilocytcs  may  be 
of  large  or  small  size,  the  varieties  of  deformities  being  infinite, 
and  the  degree  marked  or  slight  in  relation  to  the  nature  of  the 


138  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

blood  disease.  Some  of  the  cells  may  resemble  the  shape  of  a 
gourd  or  a  horseshoe,  others  may  be  drawn  out  at  both  ends  until 
they  form  a  spindle-shaped  or  oval  bod>^  while  others  appear 
sharply  beaked  at  one  or  more  points,  or  shaped  like  a  dagger  or 
the  blade  of  a  tomahawk.  Occasionally  ver}-  minute,  rapidly- 
oscillating,  rod-shaped  forms  are  seen,  morphologically  not  un- 
like large,  unstained  bacilli — the  psetido-bacilli  of  Hay  cm.  These 
rod-shaped  forms  are  products  of  corpuscular  fragmentation,  and 
indicate  lowered  vitality  and  feeble  powers  of  resistance  to  the 
pathological  influences  affecting  the  cells. 

Poikilocytosis  is  not  characteristic  of  any  single  disease  of  the 
blood,  but  it  is  generally  most  marked  in  the  grave  forms  of 
primar)'  anemia,  such  as  leukemia  and  pernicious  anemia.  Oval- 
shaped  red  cells  are  considered  by  Cabot  ^  as  particularly  abundant 
in  the  latter  disease. 

The  conditions  of  deformity,  affecting  the  shape  and  size  of  the 
erythrocytes  are  nearly  always  associated.  As  a  general  rule,  it 
may  be  stated  that  in  the  milder  types  of  anemia  small -sized, 
slightly-deformed  poikilocytes  and  microcjtes  are  most  common  ; 
and  that  in  the  severe  forms,  large-sized,  conspicuously-distorted 
poikilocytes  and  megaloc>i:es  predominate. 

Loss  of  color  by  the  er}^throcytes,  which  pro- 
Endoglobular  gresses  hand  in  hand  with  alterations  in  their 
Degeneration,  size  and  shape  and  other  structural  changes,  is 
regarded  as  a  degenerative  process,  of  purely 
endoglobular  nature.  It  is  observed  in  the  fresh  specimen  of 
blood  in  many  severe  anemic  conditions,  especially  in  the  anemias 
associated  with  infectious  diseases,  such  as  variola,  typhus  fever, 
and  grave  septicemia  and  pyemia. 

The  decoloration  may  commence  in  one  or  more  spots,  or  it 
may  equally  involve  the  whole  surface  of  the  corpuscle,  beginning 
at  its  center  and  spreading  progressively  toward  its  peripher}^ 
Clear,  hyaline  areas  of  oval,  round,  or  elongated  shape,  appear 
within  the  stroma,  in  some  instances  sharply  contrasting  with  the 
relatively  dark  color  of  the  hemoglobin,  but  in  other  instances 
imperceptibly  blending  with  the  tint  of  the  surrounding  cell-body. 
The  active  motility  of  these  decolorized  spots  must  be  carefully 
distinguished  from  the  ameboid  movements  of  the  young  malarial 
parasite.  Complete  decoloration  transforms  the  cell  into  a  mere 
colorless  shell  or  "  phantom,"  which  would  be  practically  invisible 
were  it  not  for  its  faintly  colored  peripher)-.  Such  cells  are  known 
as  Poiifick" s  shadozi'  corpuscles,  or  as  HaycDi  s  achroniacytes. 

^  "  A  Guide  to  the  Clinical  Examination  of  the  Blood,"  3d  edition,  N.  Y.,  1898, 
p.  140. 


PATHOLOGICAL    CHANGES    IN    THE    ERYTHROCYTES.  1 39 

Maragliano  ^  and  Castellino  have  minutely  described  this  proc- 
ess of  decoloration,  along  with  certain  other  alterations  in  the 
structure  of  the  erythrocyte,  which  they  have  termed  endoglobu- 
lar  necrosis.  This  process  first  becomes  apparent  by  a  visible 
enlargement  of  the  central  concavity  of  the  corpuscle,  together 
with  a  simultaneous  fading  away  of  the  hemoglobin  in  this  situ- 
ation. This  central  area  of  pallor  gradually  spreads  toward  the 
periphery  of  the  cell,  until  finally  the  latter  alone  shows  evidence 
of  containing  coloring  matter.  Such  a  corpuscle  when  examined 
on  cross-section  appears  to  be  shaped  like  the  figure  8.  Frag- 
mentation of  this  delicate  rim  of  coloring  matter  may  occur,  in 
event  of  which  a  number  of  independent  rod-like  bits  of  stroma 

Fig.  36. 


Degenerative  changes  in  the  erythrocytes. 

are  formed.     The  decolorized  area  is  not  always  symmetrical,  so 
that  frequently  various  strikingly  bizai're  designs,  widely  differing 
in  shape  and  appearance,  may  be  observed.    It  has  been  determined 
that  in  the  dried  blood-film  these  areas  of  decoloration  show  a  de- 
cided affinity  for  basic  stains,  such  as  methylene-blue  and  thionin. 
Total  cellular  necrosis,  also  described  by  the 
Total         authors    mentioned    above,   represents    a   phase 
Necrosis.      of  structural    degeneration    in   the    er}^throcyte 
of  more  advanced  development  than  the  endo- 
globular  changes.     This  process  begins  with  the  development  of 
several  small  elevations  or  corrugations  in  the  stroma  of  the  cor- 
puscle, which  gradually  multiply,  increase  in  size,  and  change  in 
shape  until  the  larger  portion   of  the   cell's   surface  is  thus  de- 
formed.    Ameboid  movements  are  seen  to  begin,  as  if  the  entire 
cell  as  a  whole  were  involved,  the  final  stage  of  the  process  re- 
1  XL  Congress  f.  inn.  Med.,  Leipzig,  1892. 


I40  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

suiting  in  the  formation  of  a  poikilocyte,  from  which  body  points 
and  small  fra";ments  are  observed  to  break  off,  and  to  float  free 
in  the  plasma.  Decoloration,  starting  usually  from  a  single  point 
and  in  time  affecting  the  whole  stroma,  also  accompanies  this 
necrotic  alteration.  On  cross-section,  the  cell  appears  as  an 
elongated,  thin  rod,  with  rounded  poles. 

Endoglobular  degeneration  and  total  necrosis  of  the  erythro- 
cytes may  be  observed  in  both  normal  and  in  pathological  blood. 
In  normal  blood  they  occur  as  the  result  of  prolonged  contact 
with  the  air,  the  endoglobular  phase  becoming  first  apparent 
within  from  thirty  to  seventy  minutes,  and  the  total  necrosis  in 
from  three  to  four  hours,  after  the  preparation  of  the  specimen. 
In  pathological  blood  the  changes  are  thought  to  be  due  chiefly 
to  increased  globulicidal  properties  of  the  plasma  whereby  intra- 
vascular necrosis  is  excited,  and  partly  to  decreased  resistance 
of  the  er}'throcytes  in  consequence  of  which  their  degeneration 
is  abnormally  hastened  by  contact  with  normal  plasma,  and  by 
exposure  to  extraneous  influences.  In  disease,  it  follows  that 
they  are  demonstrable  immediately  or  ver\^  shortly  after  the  blood 
has  been  withdrawn,  and  that  the  development  of  the  changes 
occurs  with  much  greater  rapidity  than  in  normal  blood.  The 
endoglobular  changes  are  regarded  as  a  more  favorable  prog- 
nostic sign  than  the  total  necrosis,  being  usually  associated  with 
anemias  of  less  severe  character  than  those  in  which  the  latter 
process  prevails. 

The     normal    erythrocyte,    when    fixed    and 
Atypical       stained  with  the  aniline  dyes,  according  to  one  of 
Staining  Re-  the  methods  described  in  another  section,  pos- 
ACTION.         sesses  a  strong  affinity  for  a  single,  acid   stain  ; 
it  is  therefore  termed  monochroinatophilic .     When 
solutions  are   used  containing  both   acid  and   basic   dyes,  such 
as  eosin  and  methylene-blue  or  eosin  and  hematoxylin,  the  nor- 
mal erythrocyte  is  always  stained  by  the  eosin  ;  and  with  Ehr- 
lich's  triple  mixture,  which  is  so  formulated  that  acid,  basic,  or 
so-called  neutral  principle  may  be  selected  by  the  elements  sub- 
jected to  its  action,  according  to  their  affinities,  the  erythrocyte 
invariably  is  colored  by  the  orange  G  of  the  mixture.     (Plate  I.) 

In  certain  morbid  conditions  some  of  the  corpuscles  lose  their 
affinity'  for  the  acid  stain,  and  with  mixtures  of  both  acid  and 
basic  dyes  are  stained  atypically  by  either  or  both  elements. 
Such  corpuscles  are  said  to  be  polychroinatophilic.  Thus,  when 
stained  with  an  eosin  and  methylene-blue  mixture,  they  are 
tinged  a  dirty  grayish-purple  or  violet,  instead  of  the  rose  color 
of  eosin  ;  and  with  the  triple  mixture  they  may  be  stained  pur- 


PATHOLOGICAL    CHANGES    IN    THE    ERYTHROCYTES.  I4I 

pie,  or  reddish-brown,  or  pale  yellowish-pink  flecked  here  and 
there  with  shadings  of  a  darker  red,     (Plate  I.) 

In  polychromatophilic  corpuscles  the  staining  is  apt  to  be 
very  unevenly  shaded,  often  being  quite  dark  in  spots,  especially 
around  the  periphery  of  the  cell  and  the  margin  of  the  nucleus, 
if  the  cell  be  nucleated.  These  color  changes  affect  not  only 
the  protoplasm,  but  the  nucleus,  as  well,  and  are  strongly  em- 
phasized in  megaloblasts,  the  nuclei  of  which  may  show  every  sort 
of  color  combination.  The  more  deficient  the  corpuscle  in  hemo- 
globin, the  more  decided  its  polychromatophilic  tendency  ;  and 
the  more  strikingly  the  latter  is  developed,  the  more  intense  the 
cell's  affinity  toward  the  basic  element  of  the  stain. 

Polychromatophilia  may  occur  in  severe  forms  of  anemia  due 
to  any  cause,  and  it  is  especially  noted  in  two  of  the  primary  va- 
rieties— pernicious  anemia,  and  spleno-medullary  leukemia,  in 
both  of  which  conditions  the  process  is  a  prominent  character- 
istic of  the  blood-picture. 

Nucleated  erythrocytes,  or  erythroblasts,  are 
NucLEATiON.  found  in  the  blood  of  the  adult  only  during  the 
existence  of  pathological  conditions,  but  occur 
in  large  numbers  in  the  blood  of  the  fetus,  and  occasionally  in 
the  infant  during  the  first  few  days  of  life.  Being  invisible  in  the 
fresh  blood,  they  must  be  studied  in  the  dried,  stained  specimen. 
In  such  preparations  the  finer  structure  of  their  nucleus,  which 
bears  a  special  affinity  for  the  basic  aniline  dyes,  may  be  beauti- 
fully illustrated  by  the  use  of  solutions  containing  methylene- 
blue,  methyl -green,  and  hematoxylin. 

According  to  their  size  and  nuclear  characteristics  the  ery- 
throblasts  are  designated  as  normoblasts,  megaloblasts,  and  vii- 
croblasts.  Certain  intermediate  forms  are  also  common,  some- 
times termed  mesoblasts,  such  cells  being  atypical,  and  sharing 
characteristics  of  both  the  normoblast  and  the  megaloblast. 

Normoblasts.  (Plate  I.)  The  normoblast  is  a  nucleated  ery- 
throcyte of  about  the  general  size  and  shape  of  the  normal  erythro- 
cyte. In  the  commonest  variety  the  nucleus  is  round  or  ovoid  in 
shape,  very  deeply  stained,  and  situated  rather  toward  the  periph- 
ery of  the  cell  than  in  the  exact  center,  its  diameter  approximat- 
ing more  than  one-half  that  of  the  corpuscle  which  it  occupies.  In 
some  of  the  cells  it  appears  to  have  become  partly  or  completely 
extruded  from  the  protoplasm,  lying  either  somewhat  over  the 
periphery  of  the  cell,  or  being  completely  detached  from  it,  free  in 
the  plasma.  The  nucleus  may  be  single,  or  partly  divided  by 
constricting  bands  of  chromatin  into  a  figure  like  a  dumb-bell  or 
a  clover-leaf,   or  completely   divided  into  several  small,   round 


142  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

sections.  ]More  rarely,  kar\'okinesis  may  be  observed.  In  care- 
fully stained  films  it  will  be  noted  that  the  nuclear  framework  of 
the  typical  normoblast  consists  of  a  rather  sharply  defined  net- 
work of  chromatin  having  relatively  wide  intervening  open  spaces, 
so  that  the  general  appearance  of  the  nucleus  is  not  unlike  that 
of  a  coarse  net. 

The  protoplasm  of  this  cell  is  usually  of  regular  outline  along 
the  periphery,  stains  somewhat  more  intensely  than  that  of  the 
normal  er}^throcyte,  and  may  show  distinct  evidences  of  poh*- 
chromatophilia,  this  characteristic  being  especially  marked  in  forms 
with  dividing  nuclei. 

The  normoblast  is  regarded  as  the  immediate  antecedent  of  the 
normal  erythrocyte  or  normocyte,  into  which  it  becomes  trans- 
formed by  the  loss  of  its  nuclear  structure.  The  exact  manner 
in  which  the  nucleus  is  disposed  of  has  long  been  a  bone  of  con- 
tention among  histologists,  and  even  at  the  present  time  views  on 
this  question  should  be  held  but  tentatively,  notwithstanding  many 
exhaustive  investigations,  especially  those  of  the  German  school. 
According  to  the  views  of  Rindfleisch,^  it  is  lost  by  extrusion 
from  the  cell  body,  which  thus  becomes  a  normal  erythrocyte, 
while  the  free  nucleus,  to  which  a  small  fringe  of  protoplasm  still 
remains  adherent,  collects  from  the  plasma  material  by  virtue  of 
which  it  ultimately  develops  into  a  new  er>throblast.  Ehrlich  - 
believes  that  in  blood  rich  in  normoblasts  a  series  of  connected 
pictures  may  be  observed,  showing  that  the  normoblast  becomes 
transformed  into  the  erythrocyte  by  the  extrusion  or  emigration 
of  the  nucleus.  The  later  investigations  of  Neumann  and  K61- 
liker,^  however,  tend  to  prove  that  the  nucleus  is  disposed  of  by 
its  destruction  and  absorption  within  the  cell,  and  that  its  ap- 
parent extrusion  from  the  stroma  is  simply  the  result  of  mechan- 
ical influences.  Pappenheim  and  Israel  ^  also  believe  that  the 
normoblast's  nucleus  disappears  by  decay  and  solution  within  the 
body  of  the  corpuscle,  and  that  the  apparently  extruded  nuclei 
are  to  be  taken  as  an  evidence  of  the  process  of  plasmolysis,  or 
a  solution  of  the  protoplasm  of  the  cells  once  containing  nuclei. 
To  attempt  a  reconciliation  of  these  diametrically  opposed  views 
is  a  task  for  future  workers  to  undertake.  Meanwhile,  the  general 
trend  of  opinion  inclines  toward  the  theory  of  nuclear  solution 
within  the  corpuscle,  and  regards  the  so-called  free  nuclei  of  the 
normoblasts  simply  as  artefacts. 

1  Archiv.  f.  mikroskop.  Anat,  1880,  vol.  xvii.,  p.  I. 
^Loc.   cit. 

3Zeitschr.  f.  klin.  Med.,  1S81,  vol.  iii.,  p.  411. 

*  Virchow's  Archiv.,  1896,  vol.  cxlv.,  p.  587  ;  also,  Pappenheim  :  Inaug.  Dissert., 
Berlin,  1895. 


PATHOLOGICAL    CHANGES    IN    THE    ERYTHROCYTES.  1 43 

Normoblasts  exist  in  the  red  bone  marrow  of  the  normal  indi- 
vidual, but  are  found  in  the  circulating  blood  only  when  the 
marrow,  in  consequence  of  pressing  demands  made  upon  it  for 
the  rapid  manufacture  of  new  eiythrocytes,  becomes  unable  to 
furnish  an  adequate  supply  of  perfectly  developed  cells,  so  that 
some  of  these  immature,  nucleated  forms  prematurely  leave  their 
birth-place  in  the  marrow,  and  pass  into  the  blood  stream  in  com- 
pany with  large  numbers  of  mature,  non-nucleated  discs.  Normo- 
blasts are  associated  with  lesions  in  which  active  hemogenesis 
of  the  normal  type  is  stimulated,  being  the  prevailing  type  of 
erythroblast  in  the  anemias  resulting  from  hemorrhage,  and  in 
other  severe  anemias  of  a  secondary  type.  They  sometimes  ap- 
pear in  the  blood  in  successive  crops  of  large  numbers  during  the 
course  of  certain  severe  anemias,  this  phenomenon  having  been 
termed  by  von  Noorden  ^  a  blood  crisis.  Blood  crises,  which  are 
of  abrupt  onset  and  of  brief  duration,  lasting  but  a  few  hours, 
are  usually  the  direct  precursors  of  an  increase  in  the  erythro- 
cyte count  and  in  the  hemoglobin  percentage,  being  therefore 
a  favorable  sign  indicating  regeneration  of  the  blood.  They  occur 
with  especial  frequency  after  loss  of  blood  from  hemorrhage,  and 
in  chlorosis,  and  are  not  uncommon  in  long-standing  cases  of 
spleno-meduUary  leukemia  and  primary  pernicious  anemia  in 
which  diseases  periods  of  temporary  improvement  are  likely  to 
take  place  from  time  to  time. 

Megaloblasts.  (Plate  I.)  The  megaloblast  is  much  larger  in  size 
than  the  normoblast,  and  contains  a  single,  large,  pale-staining 
nucleus  which  occupies  the  greater  part  of  the  cell  body.  Both 
cell  and  nucleus  are  round  or  ovoid  in  shape,  the  diameter  of  the 
former  being  from  about  1 1  to  20  fi,  and  that  of  the  latter  from  6 
to  \o  p..  The  greatest  extremes  of  these  measurements  apply  to 
those  forms  which  are  seen  with  relative  infrequency,  for  the  meg- 
aloblast most  commonly  observed  does  not  usually  measure  more 
than  12  /i  in  diameter,  with  a  nucleus  of  proportionate  size.  The 
nucleus,  which  may  be  situated  either  in  or  away  from  the  center 
of  the  cell,  is  composed  of  a  chromatin  network  having  relatively 
small  intervening  open  spaces,  so  that  the  nuclear  structure  is 
decidedly  more  delicate  and  less  well-defined  than  that  of  the 
normoblast.  With  the  triacid  solution  it  stains  pale  green  or 
blue,  or  it  may  show  every  sort  of  irregular  tinctorial  reaction 
to  the  aniline  dyes,  certain  portions  being  deeply  stained,  while 
other  parts  are  but  faintly  colored ;  the  undertone  of  green  or 
blue  is  frequently  stippled  with  fine  dots  of  purple  or  of  brilliant 
crimson,  especially  about  the  periphery;  or  it  may  be  mottled  and 

1  Charite-Annalen,  1891,  vol.  xvi.,  p.  217. 


144  ERYTHROCYTES,    BLOOD    PLAQUES,    AND    HEMOCONIA. 

splotched  here  and  there  with  areas  of  purple  or  of  dark  blue. 
The  nucleus  usually  is  sharply  differentiated  from  the  body  of  the 
cell  by  a  distinct  white  margin  which  encircles  it  and  is  thrown  out 
in  bold  relief  by  the  deep  staining  of  the  nuclear  and  cell  bodies 
on  either  side.  The  protoplasm  of  the  megaloblast  often  seems 
swollen  and  enlarged,  and  appears  to  contain  areas  of  depression 
and  elevation  at  different  points ;  it  is  sometimes  quite  round  or 
oval  in  contour,  and  sometimes  more  or  less  deformed.  It  is 
usually  polychromatophilic,  and,  like  the  nucleus,  may  show 
the  greatest  variety  of  color  combinations.  Some  cells  stain  a 
dull  brownish-yellow  color  with  deeper  shadings  of  a  burnt- 
sienna  tint  in  the  neighborhood  of  the  nucleus  and  of  the  periph- 
ery ;  others  have  an  undertone  of  crimson,  as  if  the  stain  con- 
tained an  excess  of  fuchsin,  and  are  streaked  and  dotted  with 
yellow  and  tan-colored  patches  ;  still  others  stain  a  diffuse  purple, 
blending  in  spots  into  a  light  pink. 

The  megaloblast  is  an  element  of  the  bone  marrow  of  the  young 
fetus,  and  is  totally  foreign  both  to  the  marrow  and  the  blood  of 
the  normal  adult.  According  to  the  views  of  Ehrlich,  it  repre- 
sents the  immediate  antecedent  of  the  megalocyte  into  which  it 
develops  by  the  absorption  of  its  nucleus.  Apparent  extrusion 
of  megaloblastic  nuclei  is  never  observed.  Megaloblasts  are 
found  in  the  circulating  blood  only  under  conditions  in  which  the 
blood-making  organs  have  reverted  more  or  less  to  the  fetal 
type,  so  that  their  presence  in  the  circulation  is  considered  to 
indicate  that  a  sluggish  hemogenesis  of  embrj'onal  character  exists. 
The  significance  of  megaloblasts,  therefore,  is  diametrically  op- 
posed to  that  of  normoblasts,  for,  while  the  latter  are  regarded  as 
an  expression  of  blood  regeneration,  and  are  considered  to  be  of 
favorable  prognostic  significance,  the  former  must  be  looked  on 
as  an  evidence  of  degeneration  of  the  hematopoietic  organs,  and, 
consequently,  are  of  grave  prognosis. 

Megaloblasts  are  found  in  the  blood,  almost  invariably  in  as- 
sociation with  normoblasts,  in  various  anemias  of  marked  severit}', 
but  in  only  three  conditions,  viz.,  primaiy  pernicious  anemia, 
certain  cases  of  anemia  due  to  botlirioceplialns  latiis  infection, 
and  nitrobenzole  poisoning,  have  these  cells  been  found  to  con- 
stitute the  pre\'ailing  type  of  erythroblast. 

In  typical  cases  of  pernicious  anemia  their  prevalence  is  gener- 
ally admitted  to  be  a  sign  that  in  this  disease  the  bone  marrow, 
in  consequence  of  its  reversion  to  a  fetal  type,  throws  into  the 
blood  stream  large  numbers  of  these  blood  cells  of  embr}^onal 
character,  these  degenerative  changes,  the  presence  of  megalo- 
blasts, overshadowing  the  regenerative  changes,  or  the  presence 


PATHOLOGICAL  CHANGES  IN  THE  ERYTHROCYTES. 


145 


of  normoblasts.  In  bothriocephalus  anemia,  in  which  also  the 
megaloblasts  may  outnumber  the  normoblasts,  it  is  believed  that 
the  toxines  produced  by  the  parasite  cause  changes  in  the 
hematopoietic  organs  precisely  similar  to  those  found  in  pernicious 
anemia.  In  a  single  case  of  nitrobenzole  poisoning,  reported  by 
Ehrlich  and  Lindenthal,^  large  numbers  of  erythroblasts  were 
noted ;  normoblasts  predominated  at  first,  but  in  the  later  stages 
of  the  intoxication  they  were  outnumbered  by  megaloblasts.  In 
other  grave  anemias,  notably  in  leukemia,  the  regenerative  signs 
appear  to  be  more  active  than  the  degenerative,  for,  while  in  these 
conditions  megaloblasts  are  frequently  found,  they  are  never 
numerous,  being  outnumbered  by  the  normoblasts. 

In  the  following  table  the  principal  points  of  distinction  between 
the  normoblast  and  the  megaloblast  are  emphasized  : 


Normoblast. 

Megaloblast. 

Size. 

7.5  to  10  11. 

II  to  20  //. 

Nucleus. 

Sharply  defined. 
Intensely  basic. 
Coarsely  meshed. 
Occupies  about  one-half  of 
cell-body. 

Dully  defined. 

Feebly  basic. 

Delicately  meshed. 

Occupies  greater  part  of  cell -body. 

Protoplasm. 

Sometimes     very     scanty, 
and  of  ragged  outline. 
Occasionally  polychro- 
matophilic. 

Frequently  appears  swollen  ;  out- 
line fairly  regular,  but  surface 
undulating  in  many  cells. 

Striking  tendency  toward  poly- 
chromatophilia. 

Histological 
Significance. 

Typical   of    active,    adult 
hemogenesis. 

Typical   of     sluggish,    embryonal 
hemogenesis. 

Occurrence. 

Prevailing   type  of     ery- 
throblast     in    anemias 
with   active   blood   re- 
generation. 

Prevailing  type  of  erythroblast  in 
anemias' with  megaloblastic  de- 
generation of  the  bone  marrow. 

Microblasts.  The  microblast,  which  is  the  rarest  form  of  nu- 
cleated erythrocyte,  is  a  cell  usually  not  larger  than  5  or  6  //  in 
diameter,  and  often  of  smaller  size.  It  consists  of  a  deeply  stained, 
round  nucleus  like  that  of  the  normoblast,  encircled  by  a  frag- 
ment of  ragged  protoplasm  of  a  dull  brownish-yellow  tint,  in  films 
stsiined  with  the  triacid  solution,  Microblasts  are  thought  to  be 
simply  forms  of  the  normoblast  in  a  more  or  less  advanced  stage 
of  protoplasm  degeneration,  this  process  accounting  for  the  char- 
acteristic scantiness  and  frayed-out  appearance  of  their  cell-body. 
Their  clinical  significance,  naturally,  is  identical  with  that  of  the 
normoblast. 

^Zeitschr.  f.  klin.  Med.,  1896,  vol.  xxx.,  p.  427. 
10 


146  ERYTHROCYTES,    BLOOD    PLAQUES,  AND    HEMOCONIA. 

From  what  has  been  stated  above,  it  may  be  concluded  that 
normoblasts  and  megaloblasts  constitute  two  distinct  classes 
of  nucleated  erythrocytes,  each  evidencing  a  separate  type 
of  blood-formation,  and  each  carrying  a  different  clinical  mean- 
ing. Normoblasts,  being  an  adult  type  of  cell,  hav^e  sharply 
defined,  dense,  deeply  stained  nuclei ;  megaloblasts,  being  an 
embryonal  type  of  cell,  have  poorly  defined,  delicate,  feebly 
stained  nuclei.  It  is  these  peculiarities  of  the  nuclear  structure 
that  are  all-important  in  determining  the  class  to  which  a  nu- 
cleated cell  belongs — of  more  importance,  in  fact,  than  the  size 
of  the  cell. 

Atypical  Erythroblasts.  In  some  of  the  severer  anemias,  notably 
in  spleno-medullar}^'  leukemia  and  in  pernicious  anemia,  various 
atypical  erythroblasts  are  frequently  found,  corresponding  partly 
to  one  and  partly  to  the  other  of  the  first  two  species  of  cells 
described  above.  The  so-called  "  mesoblasts,"  which  maybe  re- 
garded either  as  abnormally  large  normoblasts  or  as  abnormally 
small  megaloblasts,  are  in  some  instances  almost  as  numerous  as 
the  typical  forms  of  erythroblasts.  It  is  sometimes  impossible 
accurately  to  determine  to  which  type  such  cells  belong,  but 
usually  they  may  be  classified  by  taking  as  criteria  for  differentia- 
tion the  nuclear  characteristics  referred  to  in  the  preceding 
paragraph.  In  the  triple  stained  specimen  of  blood  the  two  fol- 
lowing commoner  forms  of  atypical  erythroblasts  may  be  rec- 
ognized : — 

1.  Corpuscles  about  8  or  10  ti  in  diameter,  containing  a  rela- 
tively large,  round  or  ovoid  nucleus,  encircled  by  a  distinct  hya- 
line ring,  and  composed  of  a  finely-meshed  chromatin  framework. 
The  nucleus  stains  a  pale  green  color,  and  is  often  filled  with 
finely  stippled  areas  of  brilliant  crimson.  The  cell-body  is  usually 
of  regular  outline,  and,  as  a  rule,  is  decidedly  polychromatophilic. 
Such  cells  may  be  regarded  as  dwarf  forms  of  megaloblasts,  with 
which  they  may  properly  be  classed  in  the  differential  count. 
(Plate  I.) 

2.  Corpuscles  about  1 2  to  1 5  /i  in  diameter,  having  a  small, 
coarsely-meshed  nucleus  not  exceeding  2  or  3  /i  in  diameter,  and, 
as  a  rule,  situated  eccentrically.  The  nucleus  stains  greenish  or 
quite  black,  and  may  or  may  not  be  separated  from  the  proto- 
plasm by  a  colorless  zone.  The  body  of  the  cell  is  of  round  .or 
ovoid  shape,  and  stains  a  dull  orange-yellow  with  shadings  of  a 
warm  brown  tint  near  the  periphery  and  around  the  white  peri- 
nuclear zone,  if  such  exists.  This  form  of  cell  appears  to  carry 
the  same  clinical  significance  as  the  normoblast,  with  which  it 
may  be  grouped.     (Plate  I.) 


PATHOLOGICAL    CHANGES    IN    THE    ERYTHROCYTES.  1 47 

In  certain  of  the  severe  anemias,  staining  with 

Granular  methylene-blue  shows  a  pecuHar  granular  condi- 
Degeneration.  tion  of  the  protoplasm  in  some  of  the  erythro- 
cytes, attention  first  having  been  called  to  this 
fact  by  von  Noorden/  who  demonstrated  the  basophilic  charac- 
ters of  such  granules,  and  described  their  occurrence  in  vari- 
ous pathological  states.  Many  of  the  corpuscles  thus  affected 
are  of  the  nucleated  form,  but  non-nucleated  cells  may  be  simi- 
larly granulated  ;  as  a  rule,  such  corpuscles  are  also  strikingly 
polychromatophilic. 

The  granules  appear  either  as  fine  or  as  coarse,  stippled  areas, 
staining  intensely  with  the  basic  stain,  and  distributed  through 
the  body  of  the  cell  either  quite  uniformly,  or  in  localized  patches 
at  one  or  at  several  points.  In  some  cells  they  are  exceed- 
ingly fine  and  closely  packed  together,  so  that  at  first  glance  the 
whole  protoplasm  appears  to  be  a  homogeneous  mass  of  pur- 
plish discoloration  ;  in  others  the  protoplasm  is  dotted  here 
and  there  with  coarse  granules,  not  more  than  thirty  or  forty 
being  found  in  the  whole  cell;  still  others  may  contain  both 
fine  and  coarse  granules  irregularly  sprinkled  over  the  surface. 
(Plate  I.) 

The  occurrence  of  somewhat  similar  granulations  in  the  eryth- 
rocytes of  the  embryo  has  been  noted  by  Engel,^  Pappenheim,^ 
and  others,  who  regard  them  as  nuclear  debris,  the  product  of 
nuclear  disintegration.  Such  an  origin  in  embryonic  blood  is 
probably  physiological.  In  post-uterine  life,  however,  this  proc- 
ess is  to  be  regarded  as  a  sign  of  stroma  degeneration,  arising 
in  all  likehhood  through  the  influence  of  various  blood-poisons. 
In  some  instances  the  change  precedes  all  other  recognizable  al- 
terations in  the  blood,  and  appears  as  the  first,  and,  indeed,  some- 
times the  only,  distinct  sign  of  anemia. 

Granular  basophilia  of  the  erythrocytes  has  been  noted  with  more 
or  less  constancy  in  these  conditions  :  pernicious  anemia,  leukemia, 
Hodgkin'  s  disease,  so-called  tropical  anemia,  malarial  fever,  sepsis, 
carcinoma,  long-standing  suppurative  lesions,  and  chronic  lead- poi- 
soning. In  chlorosis,  if  uncomplicated  by  symptoms  of  intestinal 
auto-intoxication,  the  erythrocytes  do  not  exhibit  this  alteration  ; 
granule  cells  are  also  absent  in  syphilis,  in  acute  infectious  diseases, 
in  chronic  lesions  of  the  kidney  and  the  liver,  and  in  diabetes,  ac- 
cording to  Grawitz.*     Regarding  the  occurrence  of  this  change 

iQiarite-Annalen,  1892,  vol.  xvii.,  p.  202. 

^Verhandl.  d,  Vereins  f.  innere  Med.  z.  Berlin,  1898-99,  vol.  xviii.,  p.  216. 

3  Loc.  cit. 

^  Am.  Journ.  of  Med.  Sc,  1900,  vol.  cxx.,  p.  277. 


148  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

in  pernicious  anemia,  Ehrlich  ^  believes  that  the  number  of  gran- 
ule cells  in  the  blood  bears  a  certain  relation  to  the  severity  of 
the  disease,  stating  that  they  decrease  and  often  disappear  during 
the  periods  of  remission,  reappearing  as  the  other  blood  changes 
again  become  evident.  On  the  other  hand,  Litten,"  who  asserts 
that  he  has  found  these  basophilic  granulations  in  one-tenth  of 
all  cases  of  anemia,  has  been  unable  to  determine  their  clinical 
significance  from  either  a  diagnostic  or  a  prognostic  point  of  view. 
The  studies  recently  completed  by  Grawitz  and  Hamel  ^  show 
that  granular  degeneration  of  the  er)^throcytes  occurs  with  great 
regularity  in  satutniism,  both  in  obscure  and  in  well-marked  cases, 
and  these  authors  attach  considerable  diagnostic  value  to  this  fact, 
concluding  that  the  sign  is  important  in  the  diagnosis  of  lead- 
poisoning  in  patients  in  whom  the  intoxication  is  merely  sus- 
pected, being  evidenced  by  no  other  definite  symptoms. 

Oligocythemia,  or  diminution  in  the  number  of 

Oligocy-       erythrocytes  below  the  normal  standard,  is  pres- 

THEMIA.        ent  to  a  more  or  less  narked  degree  in  all  forms 

of  anemia,   being  associated,  naturally,   with  an 

oligochromemia,  or  diminution  in  the  percentage  of  hemoglobin, 

but  not  necessarily  with  an  oligemia,  or  reduction  in  the  volume 

of  the  blood-mass. 

The  loss  of  corpuscles  may  be  slight  or  it  may  be  marked,  ac- 
cording to  the  nature  of  the  anemia  of  which  it  is  symptomatic. 
The  most  striking  examples  of  oligocythemia  are  encountered 
after  hemorrhages  involving  the  loss  of  a  large  amount  of  blood, 
and  in  pernicious  anemia;  while  in  chlorosis,  and  in  the  majority 
of  the  secondary-  anemias  the  decrease  is  relatively  less  marked. 
The  following  summary  of  the  averages  of  fifty  consecutive 
counts  each  in  cases  of  primary  and  secondary  anemia,  illustrates 
the  various  degrees  of  cellular  loss  which  ordinarily  accompany 
these  conditions : 

Average  of  50  counts.  Erythrocytes  per  cb.  mm. 

In  pernicious  anemia 1,152,470 

''  leukemia 2,729,763 

"  secondary  anemia 3,642,900 

' '  chlorosis 4, 1 1 1  ? 000 

It  is  impossible  to  designate  the  degree  of  oligocythemia  which 
may  exist  without  a  fatal  outcome,  although  a  number  of  au- 
thorities have  attempted  to  set  fixed  limits  beyond  which  reduction 

^  Loc.  cit. 

i' Deut.  med.  ^Voch.,  1899,  vol.  xxv.,  p.  717. 

3  Deut.  Archiv.  f.  klin.  Med.,  1900,  vol.  Ixvii.,  p.  357. 


PATHOLOGICAL    CHANGES    IN    THE   ERYTHROCYTES.  1 49 

in  the  number  of  erythrocytes  is  supposed  to  cause  death.  The 
effects  of  a  blood  loss  are  so  diverse  in  different  individuals  that 
all  such  arbitrary  rules  must,  of  necessity,  prove  practically 
valueless.  It  should  be  remembered  that  while  in  some  persons 
a  comparatively  moderate  decrease  may  prove  fatal,  in  others  a 
most  astonishing  loss  is  compatible  with  life.  It  may  be  stated 
in  general  terms  that  few  individuals  recover  in  whom  a  count  of 
less  than  500,000  erythrocytes  to  the  cubic  millimeter  is  found, 
although  occasional  exceptions  to  this  rule  have  been  reported. 
Whether  or  not  an  actual,  permanent  polycy- 
PoLYCYTHEMiA.  themia,  or  an  increase  in  the  number  of  erythro- 
cytes above  the  normal  standard,  exists  is  still 
an  unsettled  question,  but  the  majority  of  authorities  maintain 
that  such  a  condition  is  due  merely  to  some  physical  change 
producing  concentration  of  the  blood,  or  unequal  distribution  of 
the  corpuscles,  in  favor  of  the  peripheral  blood-vessels.  In  health, 
it  would  not  seem  unreasonable  to  suppose  that  a  moderate  de- 
gree of  polycythemia  may  be  habitual  in  the  strong,  over-devel- 
oped adult,  whose  blood-making  organs  are  possibly  developed 
proportionately  to  the  other  parts  of  his  system.  In  pathological 
conditions  there  is  nothing  tangible  upon  which  to  base  the  belief 
that  an  actual  and  permanent  increase  in  the  number  of  erythro- 
cytes ever  takes  place,  the  polycythemia  associated  with  certain 
diseases  being  satisfactorily  accounted  for  by  coexisting  physical 
conditions,  in  no  way  peculiar  to  the  lesion  in  question.  While 
it  is  true  that  in  some  conditions  it  is  not  always  possible  to  ex- 
plain the  increase  by  purely  physical  causes,  still  there  is  no  posi- 
tive proof,  in  these  instances,  that  the  change  is  pathological. 
There  seems,  therefore,  no  evidence  to  warrant  an  arbitrary  clas- 
sification of  polycythemia  into  two  divisions,  actual  and  relative, 
as  some  authors  have  suggested. 

The  cause  of  polycythemia,  then,  may  be  attributed  to  physio- 
logical factors  such  as  concentration  of  the  blood,  peripheral 
stasis,  increased  viscidity  of  the  erythrocytes,  and  their  unequal 
distribution  through  the  circulatory  system. 

The  polycythemia  associated  with  various  physiological  and 
pathological  conditions  will  be  considered  under  their  appropriate 
headings.  Briefly,  an  increase  of  erythrocytes  over  the  normal 
number  is  found  in  the  following  conditions  : — 

1.  In  the  new-born. 

2.  After  taking  food. 

3.  In  starvation. 

4.  During  resort  in  high  altitudes. 

5.  From  the  effect  of  cold  baths,  massage,  and  electricity. 


I  50  ERYTHROCYTES,    BLOOD    PLAQUES,   AND    HEMOCONIA. 

6.  From  the  administration  of  lymphagogues,  emetics,  and 
purgatives. 

7.  During  active  blood  regeneration. 

8.  During  reformation  of  an  exudate  after  aspiration. 

9.  After  urinar}^  crises,  diaphoresis,  and  emesis. 

10.  In  poisoning  by  illuminating-gas  and  by  phosphorus. 

11.  In  Asiatic  cholera,  dysentery,  and  diarrhea. 

1 2.  In  acute  yellow  atrophy  of  the  liver,  and  myxedema. 

13.  In  conditions  of  cyanosis  and  peripheral  stasis,  for  example, 
uncompensated  organic  heart-disease,  emphysema,  and  asphyxia. 

14.  After  the  transfusion  of  blood. 


V.     BLOOD   PLAQUES. 

If  a  drop  of  fresh  blood  is  examined  microscopically,  imme- 
diately after  it  has  been  taken  from  the  body,  a  few  pale,  some- 
what spherical  bodies,  much  smaller  in  size  than  the  erythrocytes, 
may  usually  be  observed.  These  bodies  are  known  as  the  blood 
plaques  or  blood  platelets.  They  are  of  homogeneous  structure, 
either  almost  colorless  or  of  a  pale  yellowish  tint,  spherical  or 
irregularly  ovoid  in  shape,  and  measure  from  i  to  3  or  4  ^t«  in 
diameter.  They  are  non-nucleated,  entirely  devoid  of  ameboid 
movement,  and  react  toward  both  basic  and  acid  aniline  dyes, 
having  an  amphophilic  affinity.  The  plaques  exist  as  free  bod- 
ies in  the  general  circulation,  but  directly  after  the  withdrawal  of 
the  blood  from  the  vessels  they  show  a  remarkable  degree  of  vis- 
cosity, by  virtue  of  which  they  tend  to  adhere  in  racemose  masses 
the  occurrence  of  which  at  or  near  the  radiating  points  of  the 
fibrin  network  has  already  been  described.  The  old  belief  that 
the  plaques  represented  a  so-called  "  third  corpuscle  "  of  the 
blood  is  not  justified,  for  it  has  been  proved  that  these  bodies  are 
not  distinct  cellular  entities,  but  rather  debris,  derived  either  from 
the  blood  corpuscles  or  from  the  plasma.  Most  authorities  re- 
gard them  as  bits  of  globular  matter  extruded  from  the  erythro- 
cytes, others  as  fragments  of  disintegrated  nuclei  of  the  leuco- 
cytes, and  still  others  as  masses  of  precipitated  globulin. 

Exposure  to  the  air  appears  to  cause  an  almost  immediate  dis- 
appearance of  the  plaques  from  the  blood,  and,  therefore,  they  are 
but  seldom  noticed  in  the  blood-film  prepared  by  the  ordinary 
methods.  To  avoid  bringing  the  blood  in  contact  with  the  air, 
it  may  be  drawn  directly  through  a  drop  of  Hayem's  solution,  or 
a  weak  solution  of  osmic  acid,  the  mixture  of  the  blood  and 
fixative  being  then  placed  upon  a  slide,  and  examined  in  the  usual 
manner.     (See  page  71.) 


HEMOCONIA.  151 

The  number  of  plaques  in  normal  blood  varies  within  wide 
limits,  accordincr  to  the  statements  of  different  authorities,  but 
about  300,000  to  the  cubic  millimeter  is  generally  considered  the 
normal  average,  and  from  180,000  to  500,000  the  range  under 
physiological  circumstances. 

The  plaques  are  generally  increased  in  pernicious  anemia,  severe 
secondary  anemias,  leukemia,  pneumonia,  arthritis  deformans, 
myelitis,  tuberculosis,  and  bubonic  plague,  and  diminished  in  hemo- 
philia, purpura,  and  acute  febrile  diseases  such  as  erysipelas,  typhus 
fever,  and  the  malarial  fevers. 

VI.     HEMOCONIA. 

Miiller^  has  called  attention  to  the  constant  presence  in  normal 
and  pathological  blood  of  small,  colorless,  refractive  bodies,  of 
spheroidal  or  dumb-bell  shape,  not  larger  than  i  /i  in  diameter. 
These  bodies,  to  which  the  terms  hemoconia  and  blood-dtist  have 
been  applied,  are  highly  refractive,  and  possess  active,  limited 
molecular  motility,  but  not  true  ameboid  motion.  They  have 
been  compared  in  appearance  to  fine  fat-droplets,  to  micrococci, 
and  to  granules  derived  from  the  protoplasm  of  the  leucocytes. 
Nothing  is  known  of  their  histological  character  and  significance, 
beyond  the  facts  that  they  are  not  concerned  in  the  process  of 
fibrin-formation,  and  that  they  are  not  fatty  bodies,  since  they  are 
neither  stained  by  osmic  acid,  nor  dissolved  by  ether.  Both 
Stokes  and  Wegefarth,^  and  NichoUs  ^  regard  them  as  free  granules 
of  the  neutrophile  and  eosinophile  leucocytes,  and  believe  that 
they  are  probably  concerned  in  the  protective  properties  of  the 
blood  in  immunity.  Stengel*  suggests  that  they  may  be  simply 
the  products  of  fragmentation  of  the  erythrocytes,  such  as  may 
be  produced  by  heating  fresh  blood  to  destructive  temperatures, 
when  bits  of  the  corpuscles  are  seen  to  bud  out,  break  off,  and 
float  free  in  the  plasma,  endowed  with  pseudo-ameboid  motility. 

Miiller  found  hemoconia  numerous  in  a  case  of  Addison's  dis- 
ease, but  these  bodies  were  very  scanty  in  a  number  of  markedly 
cachectic  conditions.  Their  occurrence  in  the  blood  appears  to 
carry  no  definite  clinical  significance. 

iCentralbl.  f.  Path.  u.  Bakteriol.,  1896,  vol.  xxv.,  p.  529. 
2 Johns  Hopkins  Hosp.  Bull.,  1897,  vol.  viii.,  p.  246. 
sPhila.  Med.  Joum.,  1898,  vol.  i.,  p.  387. 
4**  Text-book  of  Pathology,"  Phila.,  1899,  2d  ed. 


SECTION   IV. 


THE   LEUCOCYTES. 


(  Triacid  Stain.) 

1.  2,  3,  4-   Small  Lymphocytes. 

Contrast  the  faintly  colored  protoplasm  of  these  cells  in  the  triple  stained  specimen 
•with  their  intensely  basic  protoplasm  in  the  film  stained  with  eosin  and  methylene- 
blue,  17  and  18.    The  cell  body  of  i  is  invisible.    Note  the  kidney-shaped  nucleus  in  4. 

5,  6.    Large  Lymphocytes. 

With  this  stain  the  nucleus  reacts  more  strongly  than  the  protoplasm  ;  with  eosin  and 
methylene-blue  (19.  20),  on  the  contrary,  the  protoplasm  is  so  deeply  stained  that  the 
nucleus  appears  pale  by  contrast.  This  peculiarity  is  also  observed  in  the  smaller 
forms  of  lymphocytes. 

7,  8.   Transitional  Forms. 

Note  the  moderately  basic  and  indented  nucleus,  and  the  almost  hyaline  non-granular 
protoplasm.  Compare  8  with  the  myelocyte,  7,  Plate  IV,  these  cells  differing  chieHy 
in  that  the  myelocyte  contains  neutrophile  granules. 

9,  10,  II.   Polynuclear  Neutrophiles. 

These  cells  are  characterized  by  a  polymorphous  or  polynuclear  nucleus,  surrounded 
by  a  cell  body  filled  with  fine  neutrophile  granules.  In  11  the  nuclear  structure  is 
obviously  separated  into  four  parts  ;  in  9  it  is  moderately,  and  in  10  markedly,  poly- 
morphous. 

12,  13.   Eosinophiles. 

The  nuclei  are  not  unlike  those  of  the  polynuclear  neutrophile,  except  that  they  are 
somewhat  less  convoluted,  and  poorer  in  chromatin,  staining  less  intensely.  The  pro- 
toplasm is  filled  with  coarse  eosinophile  granules,  the  characteristics  of  which  are 
clearly  illustrated  by  13,  a  "  fractured  "  eosinophile. 

14.  Eosinophilic  Myelocyte. 

Compare  with  15. 

15,  16.    Myelocytes.     {Neutrophilic.) 

These  cells  are  morphologically  similar  to  14,  except  that  they  contain  neutrophile 
instead  of  eosinophile  granules.  Note  that  the  granules  of  the  myelocyte  are  identical 
with  those  of  the  polynuclear  neutrophile.  h.  dwarf  form  of  myelocyte  is  represented 
by  16. 

{Eosi7i  and  Methylene-blue.) 

17,  18.   Small  Lymphocytes. 

Note  the  narrow  rim  of  pseudo-granular  basic  protoplasm  surrounding  the  nucleus, 

and  the  pale  appearance  of  the  latter. 
19,  20.   Large  Lymphocytes. 

Budding  of  the  basic  zone  of  protoplasm  is  represented  by  20.     Both  of  these  cells 

belong  tf>  the  same  type  as  5  and  6. 
21,  22.   Large  Mononuclear  Leucocytes. 

Compared  with  19  and  20,  these  cells  have  a  decidedly  less  basic  protoplasm,  but  a 

somewhat  more  basic  nucleus.     In  the  triple  stained  film  these  differences  cannot  be 

detected,  so  that  they  must  be  classed  as  large  lymphocytes. 

23,  Transitional  Form. 

The  distinction  between  this  cell  and  24  is  not  marked  ;  the  nucleus  of  the  latter 
simply  being  somewhat  more  basic  and  convoluted. 

24,  25,  26,  27.    Polynuclear  Neutrophiles. 

With  this. stain  these  cells  show  a  feebly  acid  protoplasm,  and  lack  granules.  Note 
that  the  more  twisted  the  nucleus  the  deeper  it  is  stained.   Compare  with  9, 10,  and  11. 

25,  29.    Eosinophiles. 

Compare  with  12  and  13. 

30.  Eosinophilic  Myelocyte. 

Compare  with  14. 

31.  Basophile.     {Finely  granular.) 

This  cell  is  characterized  by  the  presence  of  exceedingly  fine  5-granules,  staining  the 
pure  color  of  the  basic  dye.    The  nucleus  is  markedly  convoluted  and  deficient  in 
chromatin.     The  cell  here  shown  was  found  in  normal  blood. 
32,33,34,35,36.    Mast  Cells.  •      •       •• 

The  granules  take  a  modified  basic  color,  as  shown  by  their  royal-purple  tint  in  this 
illustration.  Note  their  unusually  large  size  and  ovoid  shape  in  35,  their  peculiar 
distribution  in  35  and  36,  and  their  irregularity  in  size  in  32  and  36.  With  the  triacid 
mixture  these  granules,  as  well  as  those  of  the  finely  granular  basophile,  31,  remain 
unstained,  showing  as  dull-white  stippled  areas  in  the  cell  body.  The  nuclear  chro- 
matin of  the  mast  cell  is  so  delicate  and  so  feebly  stained  that  it  is  barely  visible. 
These  cells  were  found  in  the  blood  of  a  case  of  spleno-medullary  leukemia. 


PLATE  II. 


""^M^ 


10, 
14 


o*l  «... 

,foo»ooo'o 


«„•?. 


1 1 4^^,^-?ft>< 


ih^^ 


12 


!S^^^ 


16 


♦;•  ;v'  .•{..  •    .'c 


21 


22 


17  18 


OOi 


23 


28 


29 


26 


30 


<f 


27 


^ 


0 


35 


36 


^fiti 


The  Leucocytes. 
(i-i6,  Triacid  Stain  ;  17-36,  Eosin  and  MetJiylene-blue.) 

(E.  F.  Faber,/^c.) 


SECTION   IV. 
THE    LEUCOCYTES. 


I.    GENERAL   CHARACTERISTICS. 

In  the  fresh,  unstained  blood-film  the  leuco- 
Appearance    cytes  are  recognized  as  pale  nucleated  cells,  the 
IN  majority   of  which  are   larger  in  size  than   the 

Fresh  Blood,  erythrocytes,  by  which  they  are  greatly  outnum- 
bered, the  proportion  of  the  former,  to  the  latter 
ranging  approximately  between  i  1450  and  i  :  1,200  in  normal 
blood.  The  size  of  the  normal  white  corpuscles  varies  from 
about  7 //  to  10  or  12  fi  in  diameter,  and  their  shape,  while  in 
the  resting  stage,  is  irregularly  round  or  oval. 

By  careful  examination  four  different  varieties  of  these  cells 
may  be  distinguished,  the  distinction  between  these  forms  being 
made  more  striking  by  the  addition  of  a  small  quantity  of  a  one 
per  cent,  acetic  acid  solution  to  the  fresh  film.  These  varieties, 
which  are  essentially  the  same  as  those  first  described  by  Schultze, 
in  1865,^  are  as  follows  : — (i)  Non -ameboid  cells  about  the  size 
of  the  normal  erythrocyte,  consisting  of  a  pale,  compact,  spher- 
ical nucleus,  encircled  by  a  narrow  zone  of  homogeneous  proto- 
plasm. (2)  Ameboid  cells  almost  twice  the  size  of  the  erythro- 
cyte, consisting  of  a  rather  coarsely-meshed  nucleus,  spherical, 
ovoid,  or  indented  in  form,  surrounded  by  a  relatively  large 
amount  of  clear  protoplasm.  The  latter  is  highly  opaque,  for 
although  it  forms  an  exceedingly  thin  layer  when  spread  out  flat, 
it  effectually  obscures  the  outlines  of  objects  over  which  it  lies — 
as  an  explanation  for  which  characteristic  Kanthack  and  Hardy " 
presume  that  the  cell  matter  is  composed  of  a  colorless  basis 
embedding  immense  numbers  of  minute  vacuoles  filled  with  a 
substance  of  a  different  refractive  index.  (3)  Ameboid  cells  of 
slightly  smaller  size  than  the  second  variety,  consisting  of  a  single 
twisted  nucleus,  or  of  two  or  more  separate  round  or  ovoid  nuclei 
embedded  in  a  body  of  protoplasm  crowded  with  exceedingly 
delicate,  moderately  refractive  granules.  The  nuclear  network  is 
composed  of  chromatin  threads  closely  united  to  form  a  compact, 
lobulated  structure,  and  the  protoplasm  appears  to  d^nsist  of  a 

^Archiv.  f.  mikr.  Anat.,  1865,  vol.  i.,  p.  i. 
2Journ.  of  Physiol.,  1894-95,  vol.  xvii.,  p.  81. 


156  THE    LEUCOCYTES. 

transparent  substance,  of  gelatinous  character,  having  a  refractive 
index  but  slightly  below  that  of  the  granules  which  it  contains. 
(4)  Ameboid  cells  containing  a  convoluted  nucleus,  or  several 
spherical  nuclei,  embedded  in  a  protoplasm  filled  with  coarse, 
highly  refractive,  fat-like  granules.  The  nuclear  structure  con- 
sists of  a  coarsely-meshed,  knotted  network,  and  the  protoplasm 
is  much  less  refractive  than  its  granules,  being  clear  and  struc- 
tureless in  appearance. 

Spontaneous  changes  in  the  shape  of  the  larger 
Ameboid       v-arieties  of  leucocytes  may  be  observed  if  the  slide 

Movement,  is  placed  upon  a  warm  stage  having  a  temper- 
ature of  about  98.5°  F.  During  these  ameboid 
movements  the  shape  of  the  cells  constantly  undergoes  alteration, 
by  the  alternate  contraction  and  expansion  of  the  protoplasm. 
Tentacular  processes  reach  out  from  various  portions  of  the 
cell  body,  while  at  other  points  its  surface  becomes  retracted, 
so  that  it  may  appear  as  an  irregular  nucleated  mass  provided 
with  one  or  more  long,  snake -like  arms  projecting  from  a 
central  body.  These  ameboid  cells  are  chiefly  concerned  in 
the  process  of  phagocytosis,  or  the  engulfing  and  destruction  of 
micro-organisms  and  other  foreign  matter  which  may  gain  en- 
trance into  the  circulating  blood,  and  to  leucocytes  which 
exert  this  function  the  term  phagocyte  has  been  applied.  The 
well-known  experiments  of  Metschnikoff  ^  have  shown  their 
propensity  for  seizing  upon  and  devouring  pathogenic  bacteria 
such  as  the  anthrax  bacillus  and  the  er^^sipelas  streptococcus, 
and  further  proof  of  such  phagocytic  action  may  be  frequently 
found  in  the  fragments  of  other  foreign  matter,  such  as  bits 
of  old  blood  clots  and  malarial  pigment,  embedded  in  their 
protoplasm. 

It  has  also  been  suggested  by  Gabritschewsky '  that  it  may  be 
possible  under  some  circumstances  that  phagocytes  are  capable 
not  only  of  engulfing  solid  bodies,  but  may  also  imbibe  and  ab- 
sorb liquid  substances,  which  are  thus  rendered  harmless  to  the 
organism,  and  to  this  property  the  term  pinocytosis  has  been 
given  by  this  author. 

The  ameboid  propert}'  of  the  leucocytes  is  also  responsible  for 
the  ease  with  which  these  cells  escape  from  the  blood-vessels  into 
the  perivascular  tissues  in  inflammator}^  lesions,  and  to  a  less  ex- 
tent in  health.  This  well-known  process  of  diapcdcsis  is  facili- 
tated by  virtue  of  the  leucocyte's  abilit}^  to  elongate  and  flatten 

1  "  L' Inflammation,"  Paris,  1892. 

=2  Annal.  de  I'lnstitut  Pasteur,  1S94,  vol.  viii.,  p.  673. 


GENERAL    CHARACTERISTICS.  I  57 

out  SO  that  it  may  readily  emigrate  through  the  spaces  between 
the  endothelial  cells  of  the  vessel-wall. 

The  identification  of  the  various  forms  of  leuco- 

Cell  cytes  depends  largely  upon  the  presence  or  ab- 

Granules.      sence  of  granules  in  their  protoplasm,  and  upon 

the  distinctive  manner  in  which  these   granules 

react  towards  the  acid,  basic,  and  so-called  neutral  solutions  of 

the  aniline  dyes.     By  means  of  this  method  of  ''  color-analysis  " 

Ehrlich  has  provided  a  rational  means  by  which  the  study  of  the 

leucocytes  may  be  undertaken. 

Five  varieties  of  granules,  which  are  designated  by  the  use  of 
the  Greek  letters  a;  /9,  ;-,  d,  and  £,  may  be  recognized  in  the  cell- 
bodies  of  the  leucocytes,  as  follows  : — 

1.  a-gramiles  (eosinophile,  oxyphile,  or  coarse  oxyphile  gran- 
ules). Coarse,  spherical  or  ovoid,  highly-refractive  granules  of 
a  peculiar  fat-like  appearance,  showing  a  striking  affinity  for  acid 
stains,  especially  for  eosin.  In  normal  blood  they  occur  only  in 
leucocytes  with  polynuclear  or  polymorphous  nuclei,  but  in  cer- 
tain pathological  conditions  they  may  be  found  in  that  variety  of 
the  leucocyte  known  as  the  eosinophilic  myelocyte. 

2.  ^-granules  (amphophile  granules).  Fine  granules  which 
are  capable  of  reacting  toward  both  acid  and  basic  dyes,  inva- 
riably staining  with  the  former  and  sometimes  with  the  latter,  if 
the  stains  are  used  singly,  while  in  a  mixture  of  the  two  they 
always  react  toward  the  acid  dye.  These  granules  never  occur 
in  normal  blood,  but  in  some  pathological  conditions  a  varying 
proportion  of  the  leucocytes  may  exhibit  amphophilic  reactions 
on  the  part  of  some  of  their  granules. 

3.  y-granules  (mast-cell,  or  coarse  basophile  granules).  Very 
coarse  granules,  measuring  from  .2  to  .4/i  in  diameter,  and  pos- 
sessing an  intense  affinity  for  basic  dyes.  If  stained  with  car- 
boltoluidin-blue,  with  thionin,  or  with  alkaline  methylene-blue, 
and  differentiated  with  glycerine-ether,  they  are  colored  a  dis- 
tinctive deep  purplish-red.  These  granules  occur  in  a  form  of 
leucocyte  known  as  the  mast-cell,  only  in  certain  rarely  observed 
pathological  states. 

4.  b-granides  (fine  basophile  granules).  Fine  granules,  stain- 
ing with  basic  dyes,  and  occurring  under  normal  conditions  in 
leucocytes  having  polymorphous  nuclei.  They  are  most  clearly 
demonstrated  with  such  basic  dyes  as  thionin  or  methylene-blue, 
by  which  they  are  stained  a  deep  blue  color. 

5.  t-granules  (neutrophile,  or  fine  oxyphile  granules).  Ex- 
ceedingly fine  granules,  formerly  thought  to  have  a  selective 
affinity  for  the  neutral   element  of  a  solution  composed  of  acid 


158  THE    LEUCOCYTES. 

and  basic  dyes,  but  now  known  to  have,  in  reality,  a  feeble  oxy- 
philic tendency.  They  occur  abundantly  in  the  normal  polynu- 
clear  neutrophile  cells,  and  also  in  several  pathological  forms  of 
leucocytes  :  the  myeloc}i:e,  the  small  mononuclear  neutrophile, 
and  the  "  small  neutrophilic  pseudolymphoc}-te." 

But  little  is  known  of  the  real  nature  and  function  of  the  leuco- 
cyte granules,  in  spite  of  their  elaborate  study  by  different  in- 
vestigators. Two  leading  views,  which  excite  much  controversy, 
to-day  command  attention  :  the  hypothesis  of  Ehrlich,^  and  the 
bioblastic  theor\^  of  Altmann."  Ehrlich  regards  them  as  an 
evidence  of  a  specific  secretory  function  on  the  part  of  the 
cells,  which  under  normal  conditions  contain  but  a  single  variety 
of  granules.  They  are  to  be  considered  as  products  of  cellular 
metabolic  activity",  and  are  destined  to  be  given  off  in  the  vicinit}^ 
of  the  cells,  this  elimination  perhaps  constituting  one  of  the  most 
important  functions  of  the  latter.  Far  from  representing  mere 
waste-products,  as  some  authors  contend,  they  are  in  realit}'  ele- 
ments of  decided,  although  obscurely-defined,  value  to  the  or- 
ganism. Altmann,  in  his  bioblastic  theor}',  considers  cell  granules 
as  definite  biological  entities,  and  believes  that  they  "  serve  as  a 
basis  for  the  explanation  of  the  many  phenomena  of  organic  met- 
abolism." In  summing  up  their  functions,  he  remarks  that  "  they 
effect  through  oxygen-transmission  both  reductions  and  oxygena- 
tion, and  in  this  manner  accomplish  the  disunions  and  the  synthe- 
ses of  the  economy  without  sacrificing  their  ow^n  individuality." 

As  a  rule,  the  cell  granules  are  thought  to  be  relatively  simple 
bodies,  although  their  exact  composition  is  as  yet  undeter- 
mined. It  has  been  proved  by  W^eiss^  and  others  that  they  are 
of  albuminous  character.  The  eosinophile  granules,  in  which 
iron  has  been  demonstrated  by  Barker^  and  other  observers,  are 
more  complex  than  the  other  varieties.  They  are  of  a  higher 
histological  structure,  consisting  of  an  external  limiting  portion 
which  may  be  clearly  differentiated  from  the  central  area.  Han- 
kin  and  Kanthack^  have  determined  the  fact  that  increased  bac- 
tericidal power  of  the  blood  is  closely  correlated  with  the  dis- 
charge of  both  eosinophile  and  neutrophile  granules  into  the 
plasma,  and  the  former  observer  ^  has  furthermore  shown  that  in 

'  Loc.  cit. 

2  "  Uber  die  Elementarorganismen  und  ihre  Beziehungen  zu  den  Zellen,"  Leipzig, 
1894,  2d  ed. 

3"  Hematologische  Untersuchungen,"  Wien,  etc.,  1S96. 

■»  Johns  Hopkins  Hosp.  Bull.,  1 894,  vol.  v.,  p.  93. 

sCentralbl.  f.  Bakt.  u.  Par.,  1S92,  vol.  xii.,  p.  777.  Ibid.,  1893,  vol.  xiv.,  p. 
852. 

sjourn.  of  Physiol.,   1894-95,  vol.  xvii.,  p.  81. 


CLASSIFICATION.  I  5  9 

experimental  infections  there  is  at  the  point  of  the  infection  an 
accumulation  of  cells  containing  eosinophile  granules,  together 
with  a  discharge  of  such  granules  during  the  conflict  of  the  cells 
with  the  invading  micro-organisms. 

In  the  normal  adult  the  number  of  leucocytes 
Normal  Num-  in  the  peripheral  circulation  averages  from  about 
BER.  5,000  to  10,000  to  the  cubic  millimeter  of  blood. 

In  the  majority  of  instances,  in  which  the  influ- 
ences of  physical  factors  are  excluded,  a  count  of  7,500  leu- 
cocytes per  cubic  millimeter  may  be  regarded  as  the  mean  nor- 
mal average.  Variations  of  several  thousand  cells  per  cubic 
millimeter  above  and  below  this  number  are  within  physiolog- 
ical limits,  and  frequently  occur  because  of  the  extreme  suscep- 
tibility of  the  leucocytes  to  agencies  causing  such  transient  fluctu- 
ations. The  following  table,  compiled  from  data  given  by  Hayem,^ 
Grawitz,^  and  von  Limbeck,^  shows  the  average  number  of  leuco- 
cytes determined  by  various  authorities  : 

Thoma 8,687  per  cb.  mm. 

Von  Limbeck 8,500 

Rieder 7,680 

Boeckman  ;  Halla 7^533 

Graeber ;    Reinecke 7,242 

Tumas 6,200 

Hayem 6,000 

Average 7j4o6 


II.     CLASSIFICATION. 

Six  distinct  varieties  of  leucocytes  may  be  recognized  in  the 
healthy  adult's  blood  stained  by  the  triacid  mixture  of  Ehrlich, 
according  to  the  method  described  in  a  previous  section.  These 
varieties,  together  with  their  normal  relative  percentages  and  abso- 
lute number  to  the  cubic  millimeter  of  blood,  are  as  follows  : — 

Variety.  Per  cent.        Number  per  cb.  mm. 

Small  lymphocytes 20-30  1,000-3,000 

Large  lymphocytes  and  tran- 
sitional forms 4—8  200-800 

Polynuclear  neutrophiles 60-75  3>ooo-7)5oo 

Eosinophiles o.  5-5  25-500 

Basophiles,  as  high  as 0.5  25 

^  Log.  cit. 

2"Klinische  Pathologic  des  Blutes,"  Berlin,  1896. 


l60  THE    LEUCOCYTES. 

The  variations  in  these  numbers  and  percentages,  which  de- 
pend upon  different  physiological  and  pathological  influences,  are 
referred  to  in  other  sections. 

The  lymphocytes,  or  small  lymphocytes,  as 
Small  they  are  commonly  designated  in  contradistinction 
Lymphocytes,  to  the  large  mononuclear  forms,  are  non-granu- 
lar cells  which  measure  from  about  5  to  10  /.«  in 
diameter,  their  average  size  being  that  of  the  normal  erythrocyte, 
or  7.5  fi  in  diameter.  The  typical  cell  of  this  class  consists  of  a 
single,  round,  deeply  staining  nucleus  surrounded  by  a  narrow 
zone  of  protoplasm,  and  sometimes  provided  with  one  or  two 
pseudo-nucleoli,  situated  eccentrically  upon  the  nuclear  surface. 
The  nucleus  is  so  relatively  large  that  it  almost  completely  fills 
the  cell,  being  its  most  conspicuous  part,  while  the  rim  of  proto- 
plasm is  usually  so  narrow  and  poorly  defined  that  at  first  glance 
it  may  escape  notice.  These  characteristics — a  relatively  large 
nucleus,  and  a  relatively  scant}^  amount  of  protoplasm — are  more 
conspicuously  exhibited  in  the  smaller  than  in  the  larger  forms 
of  these  cells. 

With  Ehrlich's  triple  stain  the  nucleus,  being  rich  in  chromatin, 
is  colored  deep  blue  or  purple,  and  the  protoplasm  is  either  en- 
tirely unstained,  appearing  as  a  narrow  hyaline  halo  surrounding 
the  nucleus,  or  it  is  tinged  a  delicate  shade  of  pink,  if  it  happens 
to  react  toward  the  acid  fuchsin  of  the  mixture. 

In  films  stained  with  eosin  and  methylene-blue  the  nucleus 
shows  a  decided  affinity  for  the  basic  dye,  usually  staining  dark 
blue,  or,  more  rarely,  pale  green.  The  protoplasm  shows  as  a 
relatively  narrow  encircling  area  of  deep  blue  color,  which  has 
been  likened  in  appearance  to  the  surface  of  ground  glass  ;  it  is 
much  more  intensely  basic  than  the  nucleus,  which  looks  pale  by 
contrast. 

Occasionally  small  lymphocytes  are  encountered  in  which  the 
nucleus  is  atypical  both  in  morphology  and  in  staining  properties. 
Thus,  some  cells  contain  a  pale,  almost  hyaline  nucleus  composed 
of  an  exceedingly  scanty  chromatin  structure  which  reacts  vQry 
feebly  to  the  basic  dyes  ;  others  contain  a  deeply  stained,  indented 
or  kidney-shaped  nucleus  similar  in  shape  to  that  of  the  so-called 
"transitional"  forms;  while  still  others  are  provided  with  a 
nucleus  which  has  evidently  become  completely  divided,  so  that 
such  a  cell  really  contains  two  distinct  hemispherical  nuclei,  rich 
in  chromatin,  deeply  stained,  and  situated  toward  the  poles  of 
the  cell  body.  These  irregular  forms  of  lymphocytes  occur  in 
both  normal  and  in  pathological  blood,  but  with  much  greater 
frequency  in  the  latter,  especially  in  both  forms  of  leukemia. 


CLASSIFICATION.  l6l 

Under  this  term   it  is  convenient  to   include 

Large         both  the  larger  forms  of  the  true  lymphocyte — 

Lymphocytes,  those  measuring  ii  //  or  more  in  diameter — and 

also  that  variety  of  hyaline  cell  known  as  the 

large  mononuclear  leucocyte.     These  two  forms  of  cells,  although 

they  are  generally  considered  as  distinct  histological  species,  one 

being  a  true  lymphocyte  and  the  other  probably  a  marrow-bred 

element,  may  for  practical  purposes  be  classed  together,  since  it 

is  impossible  to  differentiate  one  from  the  other  in  the  specimen 

prepared  for  an  ordinary  clinical  examination.^ 

Cells  of  this  type  may  range  in  size  from  1 1  to  1 5  /i  or  even 
larger  in  diameter,  and  are  usually  of  round  or  ovoid  shape,  ex- 
cept in  an  occasional  cell  where,  in  consequence  of  the  injury 
received  during  the  preparation  of  the  blood-film,  the  outline 
may  be  exceedingly  irregular  and  deformed.  The  nucleus,  which 
is  round,  ovoid,  or  somewhat  elongated,  is  generally  situated  to- 
ward the  periphery  of  the  cell  body.  In  most  of  the  cells  the 
amount  of  protoplasm  is  relatively  greater  than  that  of  the  small 
lymphocyte,  but  occasionally  this  peculiarity  cannot  be  dis- 
tinguished. 

The  nucleus,  being  poor  in  chromatin,  stains  pale  blue  with  the 
triple  stain,  and  is  usually  so  delicately  tinted  that  it  is  almost 
invisible  ;  the  protoplasm  is  faintly  tinged  with  pink,  or  with  gray- 
ish-blue, or  it  may  remain  practically  colorless,  showing  merely 
as  an  indefinite  hyaline  area  surrounding  the  nucleus. 

With  mixtures  of  a  strong  acid  and  basic  dye,  such  as  eosin 
and  methylene-blue,  the  nuclear  chromatin  stains  a  diffuse  sky- 
blue  tint,  and  the  protoplasm  exhibits  a  more  or  less  decided  af- 
finity for  the  basic  element  of  the  staining  fluid.  This  tendency 
is  very  marked  in  some  cells,  the  protoplasm  of  which  contains 
an  intensely  basic  pseudo-granular  zone  staining  much  deeper 
blue  than  the  rest  of  the  cell  body,  parallehng  the  extreme  periph- 
ery of  the  cell,  and  often  apparently  separated  from  the  nucleus 
by  a  distinct  unstained  area.  In  other  cells  this  basic  affinity  is 
not  so  conspicuous,  their  protoplasm  staining  a  diffuse  purplish 
shade  in  which  a  rose-red  tone  prevails. 

1  Some  authors,  Ehrlich  himself  among  them,  maintain  that  a  distinction  be- 
tween these  two  forms  of  cells  may  invariably  be  made  in  the  stained  specimen. 
Thus,  in  the  film  stained  with  methylene-blue,  it  is  held  that  the  true  lymphocyte,  no 
matter  what  its  size,  always  possesses  a  strongly  basic  protoplasm  and  nucleus,  the 
latter  staining  less  deeply  than  the  former  ;  while  the  large  mononuclear  leucocyte 
has  a  feebly  basic  protoplasm  and  nucleus,  the  latter  staining  mo7-e  intensely  than  the 
former.  These  points  of  difference,  although  they  may  be  distinguished  in  specimens 
stained  by  special  methods,  seem  to  be  too  finely  drawn  to  justify  their  acceptance  as 
reliable  criteria  for  the  identification  of  these  two  groups  of  cells  in  films  prepared  by 
the  technique  adapted  to  routine  clinical  work. 

11 


1 62  THE   LEUCOCYTES. 

Apparent  extrusion  of  portions  of  the  cell  body  is  not  uncom- 
monly observed,  this  phenomenon  producing  a  peculiar  ''frayed- 
out,"  ragged  appearance  around  the  periphery  of  the  lympho- 
cyte, due  to  the  partial  detachment  of  small  bits  of  the  peripheral 
seam  of  basic  protoplasm,  which  loosely  adhere  to  the  outer 
margin  of  the  cell.  Occasionally  these  small  basic  masses  be- 
come entirely  detached,  and  may  be  seen  lying  free  in  the  plasma, 
alongside  the  cell  of  which  they  were  once  a  part. 

Typical  forms  of  the  large  and  small  lymphocyte,  such  as  are 
seen  in  the  great  majority  of  stained  blood-films,  may  be  dis- 
tinguished without  difficulty,  but  in  some  diseases,  notably  in  the 
lymphatic  variety  of  leukemia,  irregular  forms  of  these  cells  are 
found,  the  size  and  nuclear  characteristics  of  which  are  so  confus- 
ingly atypical  that  it  is  sometimes  futile  to  attempt  the  classification 
of  such  hybrids  into  two  arbitrar)^  groups,  large  and  small.  Thus 
one  may  meet  with  cells  the  size  of  the  small  lymphocyte  but  hav- 
ing a  feebly  basic,  eccentric  nucleus  and  a  relatively  large  amount 
of  protoplasm  ;  and  with  cells  identical  with  the  large  lymphocyte 
except  that  they  possess  a  small,  spherical,  strongly  basic  nucleus. 
In  attempting  to  differentiate  these  atypical  forms  in  the  triple 
stained  specimen,  it  is  safe  to  be  guided  by  the  suggestions  given 
by  Thayer,^  who  is  inclined  to  place  more  emphasis  upon  the 
character  of  the  nucleus  than  upon  the  size  of  the  cell  body  as  a 
whole.  Thus,  in  a  doubtful  mononuclear,  non-granular  cell  in 
which  the  nucleus  is  similar  in  size  and  shape  to  that  of  the  small 
lymphocyte,  regardless  of  its  affinity  for  the  basic  element  of  the 
stain,  the  cell  is  classed  as  a  small  lymphocyte,  until  the  size  of 
such  a  cell  exceeds  that  of  the  polynuclear  neutrophile.  Some 
cells  no  larger  than  the  smallest  lymphocyte  may  be  classed  as 
large  lymphocytes  if  their  nuclei  are  decidedly  ovoid  in  shape, 
and  pale  in  color.  In  spite  of  every  precaution,  however, 
it  must  be  admitted  that  in  some  instances  differential  counts 
of  these  two  types  of  cells  must  be  more  or  less  inaccurate, 
for  the  obvious  reason  that  so  much  depends  upon  the  personal 
equation. 

The  so-called  transitional  forms  are  cells  which 
Transitional  closely  resemble  the  large  lymphocyte  in  shape 
Forms.         and  in  size,  but  which  differ  from  the  latter  variety 
of  cell  chiefly  in  having  a  nucleus  which,  instead 
of  being  ovoid  in  shape,  is  indented  and  drawn  out  into  the  form 
of  a  crescent  with  rounded  poles,  the  concave  aspect  of  the  nu- 
clear figure  lying  toward  the  center  of  the  cell.      In  other  forms 
the  nucleus  may  have  become  moulded  into  a  figure  resembling 
^  Johns  Hopkins  Hosp.  Reports,  1894,  vol.  iv.,  p.  103. 


CLASSIFICATION.  1 63 

an  hour-glass,  which  occupies  the  central  portion  of  the  cell 
body,  not  lying  in  contact  with  its  periphery  at  any  point. 

With  the  triple  stain  the  nucleus  of  this  cell  is  usually  stained 
somewhat  darker  blue  than  that  of  the  large  lymphocyte,  and 
the  protoplasm  is  either  quite  colorless,  or,  perhaps,  slightly 
tinged  a  grayish-blue.  With  eosin  and  methylene-blue  the  nu- 
cleus shows  a  moderately  strong  affinity  for  the  basic  dye,  being 
colored  much  darker  blue  than  the  nucleus  of  the  large,  but  dis- 
tinctly paler  than  that  of  the  small,  lymphocyte  ;  the  protoplasm 
is  stained  a  diffuse  purplish  tint,  in  which  the  pink  tinge  of  the 
eosin  conspicuously  predominates. 

Inasmuch  as  the  clinical  significance  of  the  transitional  forms 
is  identical  with  that  of  the  large  lymphocytes,  it  is  customary  to 
class  both  forms  together  under  a  single  heading,  in  the  per- 
centage table  of  the  different  forms  of  leucocytes 

Polynuclear  neutrophiles  are  cells  which,  as  a 
PoLYNUCLEAR  general  rule,  measure  from  about  lo  to  12  /i  in 
Neutrophiles.  diameter,  although  their  size  may  vary  within 
wide  limits,  some  being  not  much  larger  than 
the  small  lymphocytes,  while  others  are  nearly  twice  this  size. 
The  distinguishing  characteristics  of  these  cells  are  the  twisted, 
polymorphous  nature  of  the  nuclei  and  the  so-called  "  neutro- 
philic "  reaction  of  the  granules  which  are  embedded  in  the  pro- 
toplasm. The  nucleus  may  be  of  almost  any  shape — elongated, 
wreathed,  lobulated,  horseshoe-shaped,  or  twisted  into  designs  re- 
sembling various  letters  of  the  alphabet,  such  as  an  S,  Z,  U,  or 
E.  It  usually  consists  of  several  apparently  separate  masses  of 
irregular  shape  connected  with  each  other  by  delicate  filamentous 
strands  of  chromatin,  which  dip  beneath  the  surface  of  the  pro- 
toplasm, and,  owing  to  the  density  of  the  overlying  granules,  are 
invisible  or  but  dimly  defined  in  the  triple  stained  specimen. 
By  the  use  of  the  simpler  double  stains,  such  as  eosin  and 
methylene-blue,  the  presence  of  these  connecting  chromatin 
threads  may  be  demonstrated  with  great  clearness.  Less  com- 
monly, a  cell  contains  several  small  oval  or  round  nuclei,  which 
are  actually  separated  from  each  other,  complete  division  at  the 
points  of  constriction  having  resulted  in  the  production  of  two  or 
three,  and,  in  rarer  instances,  even  six  or  seven  distinct  nuclei. 
The  nuclear  structure  is  rich  in  chromatin,  which  forms  a  dense, 
unevenly  staining  network  possessing  a  marked  affinity  for  the 
various  basic  dyes.  It  stains  dark  blue  or  greenish-blue  with  the 
triple  stain,  and  still  more  intensely  blue  with  eosin  and  methyl- 
ene-blue solutions. 

The  fact  that  the  single,  twisted  type  of  nucleus  predominates 


164  THE    LEUCOCYTES. 

in  these  cells  has  led  to  the  current  use  of  the  adjective  *'  poly- 
morphonuclear "  as  a  substitute  for  "  polynuclear,"  but  it  is  per- 
fectly ob\ious  that  both  terms  may  be  used  synonymously,  the 
latter  perhaps  being  preferable,  because  of  its  brevit}*,  and  of  its 
established  vogue.  The  irregularity  of  the  nucleus  is  regarded 
as  a  sign  of  the  ameboid  activity  of  the  cell,  as  first  suggested  by 
Arnold,^  and  not  as  an  indication  of  degeneration,  as  formerly 
believed.  It  has  been  effectuallv  demonstrated  bv  Sherrington  - 
that  if  such  cells  are  allowed  to  quiet  down  before  they  are  killed, 
their  nuclei  usually  return  to  a  spheroidal  form. 

The  protoplasm  of  the  polynuclear  leucocyte  is  densely  packed 
with  exceedingly  fine  so-called  neutrophile  granules,  which 
stain  lavender,  or  purple,  or,  rarely,  pink,  with  Ehrhch's  triacid 
mixture,  but  which  are  usually  unstained  by  solutions  containing 
eosin  and  methylene-blue.  Kanthack  and  Hardy  ^  have  shown 
that  these  granules  have  ''a  minimal  attraction  for  acid  dyes,  or, 
briefly,  a  minimal  oxyphile  reaction,"  and,  furthermore,  that 
Ehrlich's  neutral  mixture  by  which  they  are  intensely  stained,  is 
not,  chemically  speaking,  a  neutral  stain,  but,  on  the  contrar}',  a 
powerful  and  exceedingly  differential  acid  dye,  intensely  staining 
oxyphile  granules  of  all  varieties."*  The  oxyphihc  tendency  of 
the  granules  may  be  beautifully  demonstrated  by  the  use  of 
Jenner's  eosin-methylene-blue  formula,  to  which  reference  has 
been  made.  Thus,  having  proved  that  the  granules  oi  the  poly- 
nuclear "  neutrophile  "  cell  of  Ehrlich  display  a  distinct,  although 
feeble,  affinit}'  for  acid  dyes,  and  that  they  are  unstained  by  basic 
and  neutral  dyes,  the  term  "  finely  granular  oxyphile  cell  "  has 
been  adopted  by  these  authors  for  this  vaiiety  of  leucocyte,  the 
granules  being  known  as  "  finely  granular  oxyphile"  granules. 
It  is  doubtful,  however,  if  the  use  of  these  unwieldy  terms  will 
receive  general  approval,  except  by  certain  of  the  British  school. 
To  designate  a  polynuclear  leucocyte  as  a  *'  finely  granular  oxy- 
phile cell"  is  even  more  glaringly  inappropriate  than  the  use  of 
Ehrlich's  term,  "  neutrophile,"  for  other  varieties  of  leucoc}i:es 

'  Archiv.  f.  Mikroskop.  Anat.,  1887,  vol.  xxx.,  p.  226. 

2  Proc.  Intemat.  GDngress  of  Physiologists,  Liege,  1S92. 

3Journ.  of  Physiolog}-,  1S94,  vol.  xvii.,  p.  61. 

♦  Reasoning  upon  the  basis  that  eosin  stains  with  most  striking  intensity  in  an 
aqueous  solution,  less  decidedly  in  a  glycerin  solution,  and  even  less  strongly  when 
dissolved  in  strong  alcohol,  these  investigators  distinguish  three  classes  of  oxyphile 
granules,  according  to  the  intensity  of  their  affinity  for  acid  dyes,  thus  :  (l)  Those 
which  stain  with  eosin  only  in  aqueous  solutions,  or  in  alcoholic  solutions  of  a  per- 
centage below  60  ;  (2)  those  which  stain  in  both  aqueous  and  glycerin  solutions, 
but  not  in  a  strong  alcoholic  solution  (90  to  95  per  cent.  )  of  the  dye,  and  (3)  those 
which  stain  with  aqueous,  glycerin,  and  strong  alcoholic  solutions.  They  include 
in  the  first  class,  the  neutrophile  and  the  amphophile  granules  of  Ehrlich. 


CLASSIFICATION.  165 

(/.  e.,  myelocytes,  and  ''neutrophilic  pseudolymphocytes  ")  may 
be  just  as  fittingly  described  by  the  former  phrase. 

The  granules  are  of  very  small  size,  and  of  irregular  wedge- 
or  spike-shape,  never  being  spherical  or  ovoid  in  contour.  They 
are  usually  most  densely  distributed  about  the  periphery  of  the 
cell,  whence  they  gradually  shade  off  toward  the  nucleus,  which 
is  frequently  found  to  be  encircled  by  a  perfectly  hyaline,  non- 
granular zone.  The  granules  are  not  always  confined  to  the  cell 
protoplasm,  being  scattered  over  the  nucleus,  portions  of  which 
even  may  be  partly  obscured  by  the  overlying  granular  film. 

The  jelly-like  substance  of  the  protoplasm  in  which  the  granules 
are  embedded  appears  to  show  a  slight  affinity  for  acid  dyes,  the 
intensity  of  this  affinity  varying  greatly  in  different  cells.  With 
the  triple  stain  this  reaction  is  evidenced  by  the  variable  depth 
of  fuchsin-colored  undertone  which  may  be  detected  beneath  the 
puiplish  color  of  the  granules ;  while  in  the  specimen  stained 
with  eosin  and  methylene-blue,  in  which  the  granules  are  not 
visible,  the  protoplasm  is  evenly  tinted  the  color  of  eosin. 

These  cells  are  the  most  conspicuous  of  all  the 
EosiNOPHiLES.  leucocytes,  and  may  be  at  once  identified  by  the 
presence  of  a  more  or  less  polymorphous  nucleus 
embedded  in  a  protoplasm  studded  with  coarse,  highly  refractive 
granules  which  have  a  strong  affinity  for  acid  dyes,  such  as  eosin 
and  acid  fuchsin.  Owing  to  the  large  size  of  their  granules,  and 
to  their  striking  oxyphilic  reaction,  these  cells  are  also  known  by 
the  term  ''coarsely  granular  oxyphile  cells,"  in  contradistinction 
to  the  "  finely  granular  oxyphile  cells,"  or  polynuclear  leucocytes. 
(Kanthack  and  Hardy.)  The  size  of  the  eosinophile  varies  very 
greatly,  but  most  of  them  approximate  the  size  of  the  polynuclear 
neutrophile,  or  are,  perhaps,  a  trifle  smaller.  Their  diameter 
commonly  ranges  from  8  to  1 1  //,  although  occasionally  forms 
not  larger  than  the  normal  erythrocyte  are  to  be  observed.  Their 
shape  is  usually  that  of  an  irregular  sphere,  or  oval. 

The  nucleus  may  be  kidney-  or  horseshoe-shaped,  or  twisted 
and  drawn  out  into  an  irregular  mass,  but  it  is  rarely  as  con- 
stricted and  deformed  as  that  of  the  polynuclear  neutrophile.  It 
is  nearly  always  situated  eccentrically,  cells  of  this  variety  with 
centrally  placed  nuclei  being  very  uncommonly  seen.  Occasion- 
ally the  eosinophile  contains  multiple  nuclei,  consisting  of  sev- 
eral oval  or  round  masses  between  which  no  connecting  chro- 
matin threads  can  be  distinguished,  but  usually  such  portions 
of  the  nucleus  are  joined  together  by  extensions  of  chromatin 
running  beneath  the  protoplasm.  The  nucleus  stains  faintly  in 
comparison  with  that  of  the  polynuclear  neutrophile,  although 


1 66  THE    LEUCOCYTES. 

more  intensely  than  that  of  the  large  mononuclear  cell ;  it  is  col- 
ored pale  blue  or  greenish-blue  by  the  triple  stain,  and  dark  blue 
by  eosin  and  methylene-blue  mixtures. 

The  granules,  which  are  relatively  large  in  size  and  quite  regu- 
larly spherical  in  shape  (in  contrast  to  the  delicate,  irregularly 
shaped  granules  of  the  polynuclear  neutrophile),  react  strongly 
toward  the  acid  elements  of  the  triple  stain  ;  some  are  stained 
a  brilliant  fuchsin  color,  some  deep  red,  while  others  are  brown- 
ish-yellow, or  copper  color,  or  even  black  ;  with  mixtures  of 
eosin  and  methylene-blue  they  take  the  brilliant  color  of  eosin. 
There  appears  to  be  a  marked  tendency  on  the  part  of  the  gran- 
ules to  overrun  the  nucleus,  so  that  its  morphology  in  some  cells 
is  almost  indistinguishable.  The  granules  are  also  prone  to  be- 
come readily  detached  from  the  protoplasm,  which  doubtless  ac- 
counts for  their  uneven,  blotchy  distribution  in  many  cells,  in 
which  densely  packed  granular  areas  alternate  with  open  spaces 
merely  punctuated  here  and  there  with  an  occasional  granule. 

Eosinopliiles  appear  to  offer  but  feeble  powders  of  resistance 
against  external  influences,  so  that  it  is  common  to  find  these 
cells  so  injured  by  the  process  of  making  the  film,  that  the  nu- 
cleus has  escaped  from  the  cell  body,  and  the  granules,  lying 
free  in  the  plasma,  are  scattered  about  it  in  a  cloud.  This  insta- 
bility, or  "explosive"  character  of  the  eosinophile  is  one  of  its 
most  striking  attributes,  for,  while  observed  now  and  then  in  a 
polynuclear  neutrophile,  it  occurs  with  much  greater  frequency 
in  eosinophiles  than  in  the  latter  type  of  leucocyte. 

The  protoplasm  of  the  cell  may  or  may  not  show  an  affinity  for 
the  aniline  dyes  ;  usually  it  does  not,  so  that  the  granules  appear 
to  be  embedded  in  a  perfectly  hyaline  substance  ;  occasionally 
it  is  faintly  stained  by  fuchsin,  or  by  eosin. 

Finely  granular  basophile  cells,  containing  Ehr- 

Basophile     lich's  o-granules,  are  occasionally  encountered  in 
Cells.         normal  blood,  but  with  such  rarity  that  their  real 
significance  is  not  understood. 

In  general  morphology  and  size  these  cells  resemble  the  poly- 
nuclear neutrophiles.  The  nucleus  is  invariably  twisted,  and  usu- 
ally consists  of  two  or  three  distinct  lobes  joined  by  thin  chro- 
matin bands  ;  in  the  stained  specimen  it  is  never  of  round  or  oval 
shape,  but  always  shows  evidences  of  polymorphism.  The  nuclear 
structure  is  composed  of  a  delicate,  scanty  network  of  chromatin, 
and  has  a  moderate  affinity  for  basic  dyes,  staining  dull  blue  with 
the  triple  stain,  and  pale  sea-green  with  eosin  and  methylene-blue 
mixtures. 

The  protoplasm  of  the  cell  is  closely  packed  with  fine,  irregu- 
larly shaped  granules  having  an  intensely  basic  reaction  ;  they 


CLASSIFICATION.  1 6/ 

stain  deep  blue  with  solutions  containing  methylene-blue,  but  are 
not  colored  by  the  triple  stain,  showing  in  films  stained  with 
this  mixture  as  groups  of  dull  white  spots  scattered  through  the 
cell  body.  Jenner's  stain  is  most  useful  in  bringing  out  the  char- 
acteristics of  these  granules. 

Myelocytes,  or  marrow  cells,  are  relatively 
Myelocytes,  large  round  or  oval  cells,  ranging  from  lo  to  20 
[1,  or  even  more  in  diameter,  their  average  size 
being  somewhat  larger  than  that  of  the  large  lymphocyte,  which 
they  resemble  in  general  morphology.  The  nucleus  of  the  typ- 
ical myelocyte  is  of  spherical  or  ovoid  shape,  and  is  situated 
eccentrically,  lying  distinctly  toward  one  side  of  the  cell,  so  that 
the  peripheries  of  both  cell  and  nucleus  are  often  closely  ad- 
jacent for  some  little  distance — usually  for  from  one -third  to 
one-half  of  their  course.  The  nucleus  reacts  feebly  toward  the 
basic  element  of  the  triple  stain,  being  colored  a  pale,  delicate 
sky-blue  with  this  solution  ;  it  stains  a  moderately  deep  blue  or 
purple  with  eosin  and  methylene-blue  mixtures,  and  appears  to 
be  more  coarsely  netted  and  deeply  stained  than  in  films  prepared 
by  the  preceding  method. 

In  the  smaller  forms  of  myelocytes  the  nucleus  is  frequently 
found  to  occupy  the  center  of  the  cell  body,  so  that  it  is  sur- 
rounded on  all  sides  by  a  protoplasmic  zone  of  even  width.  In 
some  of  the  larger  forms  the  nucleus  may  be  indented,  and 
moulded  along  one  margin  of  the  cell  body  like  that  of  the  so- 
called  ''transitional  "  leucocyte.  In  rare  instances  actual  division 
of  the  nucleus  appears  to  have  occurred,  so  that  two  separate 
nuclei,  each  shaped  like  a  flattened  hemisphere  and  situated  at  an 
extreme  pole  of  the  cell,  may  be  found.  Such  cells  are  often 
mistaken  at  first  glance  for  polynuclear  neutrophils,  inasmuch  as 
both  forms  of  cells  contain  multiple  nuclei  and  neutrophile  gran- 
ules ;  but  the  nucleus  of  the  polynuclear  neutrophile  is  always 
more  or  less  twisted  and  of  undulating  surface,  relatively  rich  in 
chromatin  and  stained  with  decided  intensity,  and  rarely  situated 
at  the  poles  of  the  cell,  while  the  nuclear  halves  of  this  type  of 
the  myelocyte  are  of  regular  outline  and  uniformly  close  to  the 
surface  of  the  cell,  relatively  poor  in  chromatin  and  faintly 
stained,  and  invariably  occupy  the  extreme  poles  of  the  cell  body. 
The  protoplasm  of  the  myelocyte  is  filled  with  fine  neutrophile 
granules,  such  as  occur  in  the  polynuclear  neutrophile  ;  they  are 
most  densely  distributed  at  the  periphery,  and  grow  appreciably 
less  abundant  as  they  approach  the  nucleus,  which  they  may 
overrun,  spreading  over  its  surface  like  a  thin  veil,  so  that  its 
structure  is  more  or  less  hidden. 


1 68  THE    LEUCOCYTES. 

This  one  characteristic — the  presence  of  neutrophile  granules 
in  the  protoplasm — at  once  serves  to  distinguish  the  myelocyte 
from  the  large  lymphocyte,  which  it  may  exactly  resemble  in 
size,  shape,  and  nuclear  structure  ;  the  importance  of  using  Ehr- 
lich's  triple  stain  to  differentiate  these  granules  in  specimens  used 
for  differential  counting  is  therefore  patent. 

With  the  triple  stain,  the  granules  stain  purple  or  lavender, 
exactly  like  those  of  the  polynuclear  neutrophile.  With  eosin 
and  methylene-blue  mixtures  the  protoplasm  is  stained  light  pur- 
ple, broken  here  and  there  by  indistinct,  darker  granular  areas  of 
the  same  color,  indicating  the  presence  of  basophile  granules,  in 
addition  to  those  of  neutrophile  reaction,  which  are  not  clearly 
demonstrable  with  this  stain. 

In  certain  pathological  conditions,  notably  in  spleno-medullary 
leukemia,  an  occasional  myelocyte  may  be  observed  which  con- 
tains both  fine  neutrophile  and  very  coarse  basophile  granules, 
the  latter  being  precisely  identical  in  size,  shape,  and  tinctorial 
qualities  with  Ehrlich's  j  or  mastzellen  granules.  They  are 
situated  both  in  the  protoplasm  of  the  cell,  and  over  the  nucleus. 
These  granules  are,  in  the  author's  experience,  demonstrable  only 
in  specimens  stained  by  Jenner's  method  showing  in  such  prep- 
arations as  coarse,  brilliant  purple  granules  contrasting  vividly 
with  the  paler  eosin-colored  neutrophile  granules  which  fill  the 
body  of  the  cell,  and  with  the  greenish-blue  color  of  the  nucleus. 

Eosmophilic  myelocytes,  or  myelocytes  with  a  protoplasm  filled 
\vith  coarse  eosinophile  instead  of  neutrophile  granules,  are 
common  to  several  pathological  conditions,  but  occur  with  es- 
pecial frequency  in  the  spleno-medullar}^  variety  of  leukemia,  and 
also  in  pernicious  anemia,  to  some  extent.  Such  cells  are  iden- 
tical in  size  and  morphology  of  cell  body  and  nucleus  with  the 
commoner  neutrophilic  myelocytes,  from  which  they  differ  only 
in  containing  eosinophile  granules. 

The  normal  habitat  of  the  myelocyte  is  in  the  red  bone  mar- 
row, and  its  presence  in  the  circulating  blood  must  always  be  re- 
garded as  pathological.  At  one  time  regarded  as  practically 
pathognomonic  of  leukemia,  the  myelocyte  is  now  known  to  occur 
in  many  other  conditions,  especially  those  characterized  by  pro- 
found cachexia,  by  marked  anemia,  and  by  increase  in  the  num- 
ber of  leucocytes.  The  occurrence  of  myelocytes  in  the  blood 
in  v^arious  diseases,  and  the  clinical  significance  of  these  cells  is 
discussed  in  another  place.     (See  **  Myelemia.") 

Cells   containing  Ehrlich's  j'-granules,  known 
Mast  Cells.   b>'    the    term    7nastzeUen,  or  mast  cells,  are  oc- 
casionally present  in   the  peripheral    circulation 


CLASSIFICATION.  1 69 

as  the  result  of  certain  pathological  influences,  but  are  totally- 
foreign  to  the  normal  blood  of  man.  They  are  very  commonly 
found,  sometimes  in  considerable  numbers,  in  the  spleno-medul- 
lary  type  of  leukemia,  but  are  by  no  means  invariably  associated 
with  this  disease,  being  absent  in  many  typical  cases. 

The  cells  are  of  spherical  or  ovoid  shape,  and  are  characterized 
by  a  relatively  large,  structureless  nucleus  enclosed  in  an  almost 
indefinable  protoplasm,  and  by  the  presence  of  coarse  basophile 
granules  scattered  irregularly  over  the  surface  of  the  cell — marks 
of  identification  which  remain  unchanged  whatever  the  size  of 
the  cell  may  be.  No  variety  of  cell  found  in  the  blood  exhibits 
wider  ranges  in  size.  The  forms  most  commonly  observed  meas- 
ure approximately  from  9  to  I2/^  in  diameter;  some  have  a  di- 
ameter of  fully  20  or  even  22  //,  but  cells  of  this  extremely  large 
size  are  the  exception  rather  than  the  rule ;  others  are  scarcely 
larger  than  the  small  lymphocyte,  being  but  7  or  8  //  in  diameter, 
and  these  very  small  forms  are  also  uncommon. 

The  nucleus  is  round,  oval,  or  somewhat  lobulated,  and  occu- 
pies the  greater  part  of  the  cell  body,  in  which  it  is  usually  situ- 
ated eccentrically.  Owing  to  the  similarity  in  the  appearance  of 
the  nucleus  and  the  protoplasm,  it  is  frequently  impossible  to  de- 
termine the  precise  point  at  which  the  former  structure  begins 
and  the  latter  ends,  so  that,  in  the  stained  specimen,  many  cells 
are  met  with  which  appear  to  consist  simply  of  irregular  groups 
of  granules  clinging  to  a  pale  nucleus,  every  definite  trace  of  the 
cell  body  being  lost.  (See  Plate  II,  Figs.  35  and  36.)  In  films 
stained  with  Jenner's  solution  (which  is,  by  far,  the  most  satisfac- 
tory stain  for  illustrating  the  finer  morphology  of  these  cells)  the 
nucleus  is  colored  a  beautiful,  iridescent  greenish-blue,  the  tint  of 
which  is  so  extremely  delicate  that  in  many  cells  it  is  barely  per- 
ceptible. The  staining,  though  faint,  is  even  and  clear,  indicating 
a  structure  almost  totally  devoid  of  chromatin. 

The  granules  are  invariably  large  and  coarse,  and  vary  greatly 
in  size  and  in  shape.  Some  are  smaller  than  the  granules  of  the 
eosinophile  cell,  while  others  approach  or  even  slightly  exceed 
.  5  /i  in  diameter.  They  may  be  spherical,  egg-shaped,  or  roughly 
cuboid,  the  latter  form  of  granule  being  exceedingly  common. 
A  single  type  of  granules  is  not  always  found  to  the  exclusion  of 
the  others,  for  one  cell  often  contains  granules  of  every  possible 
variety  of  shape  anfl  size  ;  this  peculiarity  is  especially  striking 
in  some  of  the  smaller  forms  of  cells  in  which  extremely  coarse 
egg-shaped  and  smaller  spherical  granules  may  be  distinguished 
clinging  to  the  periphery  of  the  nucleus  about  which  no  evidence 
of  protoplasm  is  demonstrable.     (See  Fig.  36,  Plate  II.)    In  other 


1^0  THE    LEUCOCYTES. 

forms,  both  large  and  small,  the  large  spherical  or  ovoid  granules 
may  prevail  almost  exclusively.  (See  Figs.  33,  34,  and  35,  Plate 
II.)  The  distribution  of  the  granules  through  the  cell  follows  no 
constant  rule,  but  it  is  evident  that  a  more  or  less  decided  tendency 
exists  toward  their  collection  near  the  peripher>\  They  are  al- 
ways most  densely  distributed  at  this  point,  sometimes  extending 
inward  over  the  nucleus  which  is  thus  partly  hidden,  and  some- 
times crowded  into  a  limited  zone  which  coincides  with  the  outer 
boundary  of  the  cell  for  the  greater  part  of  its  extent. 

The  granules  of  the  mast  cell  show  an  intense  affinity  for  basic 
aniline  dyes,  toward  which  they  react  metachromatically,  in  a 
highly  characteristic  manner.  With  Jenner's  solution  they  are 
stained  a  deep  royal  purple  color  in  which  the  red  tone  is  dis- 
tinctly evident,  thus  differing  from  the  granules  of  other  basophile 
cells  which  are  stained  a  pure  blue  with  this  mixture.  Dr.  H.  F. 
Harris  has  called  the  writer's  attention  to  a  still  more  distinctive 
method  of  identifying  these  granules,  by  first  staining  with  carbol- 
toluidin-blue  or  with  thionin,  and  then  by  differentiating  with 
Unna's  glycerin-ether  mixture.  In  specimens  thus  treated  the 
mast  cell  granules  are  of  a  dark  red  color,  while  other  basophile 
granules  stain  blue,  so  that  the  former  must  be  regarded  as  hav- 
ing a  modified  basic  reaction.  They  are  stained  reddish-violet 
with  Ehrlich's  acid  dahlia  solution,  and  deep  blue  with  aqueous 
solutions  of  methylene-blue.  They  are  not  stained  by  the  tri- 
acid  mixture,  and  appear  as  coarse,  dull  white  spots  through 
the  cell  body,  in  films  stained  with  this  solution.  The  distinctive 
manner  in  which  they  react  toward  selective  stains  for  mucin  has 
recently  been  discovered  by  Harris,^  who,  in  view  of  this  fact, 
suggests  that  the  term  nmcinoblast  be  applied  to  the  mast  cell. 

The  author  questions  the  identity  of  these  coarsely  granular 
basophilic  blood  cells  with  the  well-known  mast  cell  of  the  tissues, 
although  most  hematologists  consider  them  identical.  Both, 
it  is  true,  contain  granules  which  tinctorially  and  morpholog- 
ically are  identical,  but  it  is  obviously  impossible  to  determine 
cell  identity  by  criteria  such  as  these.  The  mast  cell  of  the 
tissues  differs  from  that  of  the  blood  in  having  a  nucleus  which  is 
smaller  in  relation  to  the  size  of  the  cell  body,  more  centrally 
situated,  and  richer  in  chromatin,  hence  being  more  deeply 
and  more  unevenly  stained.  The  ''explosive"  nature  of  the 
tissue  mast  cell  is  also  usually  more  striking,  for  while  cells 
with  this  tendency  are  met  with  only  occasionally  in  the  blood, 
they  seem  to  be  the  rule  rather  than  the  exception  in  the  tis- 
sues, large  numbers  of  them  consisting  of  a  nuclear  structure  sur- 

1  Phila.  Med.  Journ.,  1900,  vol.  v.,  p.  757. 


CLASSIFICATION.  I /I 

rounded  by  dense  clusters  of  granules,  which  are  frequently  drawn 
out  in  long  tentacular  extensions.  In  view  of  these  differences,  it 
may  be  well  to  be  more  specific,  by  designating  the  mast  cell 
found  in  the  blood  as  the  hemic  mast  cell. 

This  term  has  been  applied  by  Capps  ^  to  a  form 
Mononuclear  of  leucocyte  which  he  found  in  certain  cases  of 
Neutro-      general   paralysis   of  the  insane,   its   appearance 
PHILES.        in  the  blood  having  been  noted  after  apoplectiform 
attacks,  and    preceding    death.     This    cell    is  as 
large  as,  or  larger  than,  the  polynuclear  neutrophile,  contains  a 
round  or  ovoid  nucleus  which  is  deeply  stained  by  basic  dyes, 
and  has   a  protoplasm   thickly   sprinkled  with   fine  neutrophile 
granules.      Capps  suggests  that  the  cell  may  be  a  form  of  leuco- 
cyte of  slightly  more  mature  development  than  the  large  lympho- 
cyte, one  in  which  the  development  of  the  granules  has  preceded 
the  nuclear  changes.     The  close  resemblance  of  these  cells  to 
the  smaller  forms  of  myelocytes,  however,  makes  it  reasonable 
to  class  them  as  such. 

Ehrlich  has  recently  described  ^  as  a  *'  small 
Neutrophilic  neutrophilic  pseudolymphocyte "  a  cell  of  the 
PsEUDOLYM-  same  size  as  that  of  the  small  lymphocyte,  and 
PHOCYTES.  characterized  by  a  relatively  large,  round,  intensely 
basic  nucleus,  surrounded  by  a  narrow  zone  of 
protoplasm  filled  with  neutrophile  granules.  This  cell,  it  is 
maintained,  is  of  a  very  rare  occurrence,  having  been  found  in  the 
blood  only  in  a  case  of  hemorrhagic  small-pox,  and  in  the  exudate 
of  a  recent  pleural  effusion.  Ehrlich  differentiates  it  from  a  myelo- 
cyte by  its  small  size,  deeply  staining  nucleus,  and  scanty  amount 
of  protoplasm,  but  these  points  of  distinction  do  not  appear  con- 
clusive, for  many  of  the  smaller,  ''dwarf"  forms  of  myelocytes 
have  similar  characteristics.  It  does  not  appear  unreasonable, 
therefore,  to  regard  this  cell  as  an  exceedingly  small  form  of 
myelocyte,  in  which  the  nucleus  is  relatively  larger  and  richer  in 
chromatin  than  is  the  rule  in  the  larger,  more  typical  varieties. 

These  cells,  first  described  by  Tiirk^  as  '' rei- 
''  Reizungs-     zungsformen  "  (or,  literally, ''  stimulation  forms  "), 
formen."       are  said  to  occur  in  the  same  pathological  condi- 
tions in  which  myelocytes  are  found,  but  as  yet 
their  exact  significance  is  undetermined.     The  size  of  the  cell  is 
usually  midway  between  that  of  the  small  and  large  lymphocyte, 
more  often  approximating  the  size  of  the  former.     The  cell  con- 

^Amer.  Journ.  of  Med.  Sciences,  1896,  vol.  cxi.,  p.  650. 

2Loc.  cit. 

3  Cited  by  Ehrlich,  loc.  cit. 


1/2 


THE    LEUCOCYTES. 


tains  a  round  nucleus,  deficient  in  chromatin,  often  eccentrically 
placed  in  the  cell  body,  and  reacting  with  moderate  intensity  to- 
ward the  basic  aniline  dyes.  The  protoplasm  is  non-granular, 
and  stains  an  intense  brown  with  the  triacid  mixture.  Ehrlich 
suggests  that  this  cell  may  possibly  represent  an  early  stage  of  the 
er}throblast,  but  reasons  for  such  an  inference  do  not  seem  clear. 
The  writer  has  seen  such  cells  in  the  blood  of  the  post-typhoid 
anemias  of  infancy,  always  in  association  with  lymphocytosis. 

The  chief  points  of  distinction  between  the  different  forms  of 
leucocytes,  as  recognized  in  specimens  stained  with  Ehrlich' s 
triacid  mixture,  are  tabulated  below. 


Form  of  Cell. 


Size. 


Nucleus. 


Protoplasm. 


Small  lymphocyte. 


Large  mononuclear 
leucocyte,    or 
large  lymphocyte. 

Transitional  leuco- 
cyte. 


Polynuclear  neutro- 1 
phile. 


Eosinophile. 

Basophile. 
Myelocyte. 

Mast  cell. 

Reizimgsform. 


6  to    9  //. 


lo  to  15  ft. 


10  to  15  //. 


7.5  to  12^. 


7.5  to  12  ft. 


7.5  to  12fl. 


10  to  20 IX. 


7  to  22 /y. 


6  to  15^. 


Single. 
Round. 

Relatively  large. 
Dark  blue  or  purple. 

Single. 

Round  or  ovoid. 
Relatively  small. 
Ver}'  pale  blue. 

Single. 

Indented,  kidney- 
shaped,  or  cres- 
centic. 

Relatively  small. 

Pale  blue. 

Polymorphous    or 

polynuclear. 
Relatively  small. 
Moderately  dark 

blue. 
Polymorphous  or 

polynuclear. 
Relatively  small. 
Pale  blue. 
Polymorphous. 
Relatively  small. 
Dull  blue. 

Single. 

Round  or  ovoid. 

Relatively  large   or 

small. 
Very  pale  blue. 

Single. 

Round,     ovoid    or 
slightly  lobulated. 
Relatively  large. 
Very  pale  blue. 

Single. 
Round. 

Relatively  small. 
Deep  blue. 


Relatively  small  amount. 
Non-granular. 
L'nstained,  or  faint  pink. 

Relatively  large  amount. 
Non-granular. 
Unstained,  or  faint  pink 

or  grayish-blue. 
Relatively  large  amount. 
Non-granular. 
Unstained,  or  faint  pink 

or  grayish -blue. 


Relatively  large  amount. 

Contains  fine  lavender  or 
purple   neutrophile 
granules. 

Relatively  large  amount. 

Contains  coarse  red  or 
copper-colored  eosino- 
phile granules. 

Relatively  large  amount. 

Contains  fine  basophile 

granules,  unstained. 

Relatively  large  or  small 
amount. 

Contains  fine  lavender 
or  purple  neutrophile 
granules. 

Relatively  small  amount. 

Contains  coarse  baso- 
phile granules,  un- 
stained. 

Relatively  large  amount. 
Non-granular. 
Intense  brown. 


CLASSIFICATION.  1/3 

Two  different  views  are  current  at  the  present 
Origin  and    time  regarding  the  origin  and  development  of  the 

Develop-      leucocytes,  the  first  being  that  of  Ehrlich  ^  and 

MENT.  his  followers,  and  the  second  that  maintained  by 

the  Russian -school,  led  by  Uskow^  and  his  pupils. 

According  to  Ehrlich's  teachings,  the  small  lymphocyte  and 
its  mother-cell,  the  large  lymphocyte,  are  developed  in  the  lym- 
phatic tissues  in  the  various  parts  of  the  body,  wherever  such 
structures  exist.  The  large  mononuclear  leucocytes  and  transi- 
tional forms  are  considered  probably  of  myelogenous  origin. 
The  polynuclear  neutrophiles  are  thought  to  develop  exclusively 
in  the  bone  marrow,  the  great  majority  being  evolved  from  the 
neutrophilic  myelocytes  of  this  tissue,  while  a  very  limited  num- 
ber perhaps  arise  from  the  non-granular  large  mononuclear  cells. 
The  eosinophiles  develop  from  the  eosinophilic  myelocytes  in  the 
bone  marrow,  while  the  basophilic  leucocytes  similarly  have  their 
origin  in  basophilic  marrow  antecedents.  Thus,  it  is  maintained 
that  all  varieties  of  leucocytes  may  be  classed  in  two  distinct 
groups  which  have  separate  origins,  functions,  and  relations. 
The  first  group  consists  of  the  lymphocytes,  large  and  small, 
which  are  produced  solely  by  the  lymphatic  tissues ;  and  the 
second  group  includes  the  mononuclear  leucocytes  and  transi- 
tional forms,  the  polynuclear  neutrophiles,  the  eosinophiles,  and 
the  basophiles,  all  of  which  cells  are  produced  exclusively  by 
the  marrow.  Cellular  reproduction,  except  in  rare  instances, 
does  not  take  place  in  the  circulating  blood  stream. 

The  scheme  devised  by  the  Russian  school  contends  for  the 
continuous  evolution  of  the  leucocyte  from  its  earliest  to  its  most 
mature  stages.  Accordingly,  all  varieties  of  the  leucocyte,  except 
the  basophilic  cells  of  which  no  account  apparently  is  taken,  are 
but  different  developmental  stages  of  one  and  the  same  cell. 
The  youngest  form  of  leucocyte,  the  small  lymphocyte,  originates 
in  the  lymph  glands,  the  lymphocytic  bone  marrow,  and  the 
spleen,  from  which  sources  of  origin  it  reaches  the  circulation. 
The  small  lymphocyte  enlarges  until  it  becomes  identical 
in  appearance  with  the  cell  recognized  as  the  large  lymphocyte, 
its  nucleus  at  this  period  of  its  growth  having  become  somewhat 
less  intensely  basic,  although  the  basic  affinity  shown  by  the  cell- 
protoplasm  is  unaltered.  The  large  lymphocyte  in  turn  under- 
goes a  simple  increase  in  size,  its  nucleus  meanwhile  becoming 
progressively  paler  and  its  protoplasm  more  feebly  basic,  until 

^Loc.  cit. 

2  *  *  The  Blood  as  a  Tissue, "  1 890.  ( Russian. )  Also  series  of  articles  by  Uskow'  s 
pupils  in  Archiv.  d.  Sc.  Biol.,  St.  Petersburg,  1893-97. 


174  THE    LEUCOCYTES. 

it  develops  into  the  large  mononuclear  form.  The  nucleus  of 
the  latter  now  becomes  indented  and  moulded  into  a  roughly 
crescentic  figure,  its  nuclear  and  protoplasmic  characteiistics  re- 
maining unchanged,  and  the  so-called  transitional  form  thus  origi- 
nates— a  type  of  cell  which  is  regarded  as  the  immediate  ante- 
cedent of  the  polynuclear  neutrophile.  During  the  next  stage  of 
development  the  size  of  the  transitional  cell  decreases,  and  the 
whole  cell  becomes  ameboid ;  the  nucleus  becomes  denser,  more 
basic,  and  polymorphous  or  polynuclear  ;  while  the  protoplasm 
loses  the  last  trace  of  its  basic  tendency,  and  becomes  sprinkled 
with  fine  neutrophile  granules,  until  finally  the  mature  form  of 
leucocyte,  the  polynuclear  neutrophile,  is  fully  developed.  The 
final,  or  **  over-ripe  "  stage  of  the  leucocyte  is  represented  by  the 
eosinophile,  which  is  thought  to  be  derived  from  the  polynuclear 
form,  by  a  transformation  of  the  latter's  neutrophile  into  eosino- 
phile granules.  It  is  maintained  that  these  transitions  from  one 
form  of  cell  to  the  other  occur  partly  in  the  circulating  blood, 
and  partly  in  the  blood-forming  tissues,  most  largely  in  the 
latter. 

It  is  beyond  the  province  of  this  book  to  discuss  the  merits 
and  demerits  of  these  two  opposing  views,  but  it  may  be  remarked 
that  Uskow's  theory,  which  up  to  the  advent  of  Ehrlich's  observa- 
tions, commanded  general  attention  among  hematologists,  is  now 
being  rapidly  supplanted  by  the  latter.  The  investigations  of 
h^hrlich  in  this  direction  constitute  the  only  dependable  means 
by  which  many  of  the  pathological  changes  in  the  leucocytes 
may  be  explained,  and  his  views  may  be  accepted  on  the  whole 
as  accurate. 

In  all  purulent  conditions,  as  well  as  in  many 
Iodine         other  diseases,  the  protoplasm  of  the  leucocytes 

Reaction.      shows  a  more  or  less  pronounced  affinity  for  io- 
dine, as  demonstrated  b}'  staining  with  a  weak  so- 
lution of  this  metal.      For  this  pui-pose   Goldberger  and  Weiss* 
ha\e  recommended  the  following  reagent  : 

Iodine i 

Potassium  iodide 3 

Distilled  water loo 

Mix  and  add  sufficient  gum  arable  to  make  a  syrupy 
mixture. 

With  a  camel's  hair  brush  a  layer  of  this  solution  is  painted 
over  the  surface  of  the  dried,  unfixed  blood-film,  upon  which  it 
is  allowed   to  act  for  from  one  to   five   minutes.      The  excess  is 

»  Wien.  klin.  Woch.,  1S97,  vol.  x.,  p,  601. 


CLASSIFICATION.  1/5 

then  removed,  by  blotting  with  a  bit  of  filter-paper,  and  the  speci- 
men is  mounted  in  cedar-oil. 

In  films  thus  treated  the  iodine  reaction  is  recognized  by  a 
slight  or  intense,  diffuse  brown  coloring  of  the  entire  protoplasm, 
or  by  the  presence  throughout  the  protoplasm  of  numerous  in- 
tensely stained,  reddish-brown  granules,  the  latter  change  being 
the  more  common.  In  normal  blood  the  protoplasm  of  the  leu- 
cocytes is  stained  a  pale  yellow,  and  the  nuclei  remain  almost 
colorless. 

The  above  reaction,  which  is  constant  in  all  piindcnt  conditions, 
persists  as  long  as  the  suppurative  focus  exists,  but  its  intensity 
appears  to  bear  no  parallelism  to  the  extent  of  the  pus  col- 
lection. It  is  absent  in  p^ire  tnberadons  abscesses.  It  is  also 
present  with  great  constancy  in  puerperal  sepsis  and  in  other 
forms  of  septicenna,  and  frequently  in  pneianonia,  in  pidmonary 
tubercidosis,  in  malignant  disease,  and  occasionally  in  marked  ca- 
chexias. Hofbauer^  found  iodinophile  granules  in  the  leucocytes 
in  all  cases  o( pernicions  anemia,  their  number  being  greatest  in 
the  gravest  cases  ;  they  were  also  present  in  severe  forms  of  sec- 
ondary anemia,  and  in  Iciikeuiia,  but  were  absent  in  chlorosis, 
and  in  pseudoleukemia.  This  author  also  observed  numerous 
iodine-stained  extracellular  masses  in  a  case  of  purpura  hemor- 
rhagica. Kaminer  ^  believes  that  the  reaction  depends  upon  three 
factors  for  its  production — pyrexia,  leucocytosis,  and  toxemia, 
and  that  it  is  caused  by  the  action  of  some  unknown  chemotactic 
substance.  He  has  also  apparently  shown  that  the  brownish-red 
color  of  the  reaction  does  not  depend  upon  the  presence  of  gly- 
cogen in  the  leucocytes,  as  most  observers  have  claimed,  since  in 
four  cases  of  diabetes  mellitus  the  test  was  negative. 

The  practical  value  of  this  test  is  limited,  in  view  of  the  many 
different  circumstances  under  which  it  may  prove  positive.  Its 
constancy  in  purulent  conditions,  however  slight  in  extent  the 
focus  of  pus,  may  be  of  some  use  in  diagnosing  a  deep-seated 
abscess,  if  other  causes  which  also  may  give  rise  to  the  reaction 
can  be  ruled  out.  Its  absence  in  pure  tuberculous  abscess  and 
its  presence  in  all  other  forms  of  abscess  may  aid  in  distinguish- 
ing between  the  two,  and  of  ascertaining  whether  a  mixed  infec- 
tion exists.  Although  the  writer  has  followed  out  rather  at  length 
the  suggestion  made  by  Hotbauer,  that  the  intensity  of  the  reac- 
tion serves  as  an  index  to  the  severity  of  an  anemia,  the  results 
from  this  study  have  not  shown  the  reliability  of  such  a  presumption. 

iCentralbl.  f.  inn.  Med.,  1900,  vol.  xxi.,  p.  153. 

2  Deut.  med.  Woch.,  1899,  vol.  xxv.,  p.  235.  See  also  Berl.  klin.  Woch. ,  1899, 
vol.  xxxvi. ,  p.  119. 


1/6  THE    LEUCOCYTES. 

Neusser/  in  1894,  described  certain  basic 
Perinuclear  granules  about  the  nuclei  of  the  leucocytes, 
Basophilia,  which  he  regarded  as  pathognomonic  of  the  uric 
acid  diathesis,  asserting  that  this  so-called  ''peri- 
nuclear basophilia"  could  be  demonstrated  constantly  in  gout, 
lithiasis,  rheumatism,  leukemia,  and  a  number  of  other  diseases. 
These  statements  were  soon  corroborated  by  Kolisch,^  and  for  a 
time  enjoyed  more  or  less  general  credence.  The  later  researches 
of  Futcher  ^  and  of  Simon,^  however,  have  entirely  disproved  the 
claims  of  Neusser  and  his  school,  for  these  investigators,  working 
independently,  have  proved  that  perinuclear  basophilia  is  not 
only  quite  uncharacteristic  of  the  uric  acid  diathesis,  but  that  it 
can  be  constantly  demonstrated  in  every  sort  of  blood,  whether 
from  healthy  or  from  diseased  persons.  It  is  now  clear  that 
Neusser' s  granules  are  simply  artefacts,  due  to  some  slip  in  the 
technique  of  staining.  Ehrlich  ^  believes  that  their  presence  is 
but  rarely  noted,  if  perfectly  pure  crystalline  dyes  are  used  in 
preparing  the  stain. 

III.     LEUCOCYTOSIS. 

Leucocytosis  may  be  described  as  an  increase  above  the  normal 
standard  in  the  number  of  leucocytes  in  the  peripheral  blood,  this 
change  either  (a)  involving  both  a?i  absolute  and  relative  increase 
in  the  polymiclear  neiitrophile  cells  with  a  conseqne?it  I'elative  dimi- 
7iutio7i  in  the  proportion  of  mono7iuclear  non-graimlarfonns,  or  {b) 
affectijig  all  varieties  of  leucocytes  alike. 

A  leucocytosis  of  the  first  kind,  also  termed  a  polynuclear  neu- 
trophile  leucocytosis,  is  by  far  the  more  common  of  the  two  types  ; 
it  may  be  symptomatic  either  of  pathological  or  of  physiological 
conditions,  being  found  almost  invariably  in  the  former,  and  fre- 
quently in  the  latter.  A  leucocytosis  of  the  second  kind,  or  a 
general  increase  unattended  by  any  disturbance  in  the  normal 
relative  proportions  of  the  different  forms  of  cells,  is  compara- 
tively rare ;  it  is  more  frequently  dependent  for  its  production 
upon  physiological  than  upon  pathological  factors,  but  it  may 
occur  under  either  of  these  circumstances. 

From  these  facts  it  is  obvious  that  simply  an  increase  in  the 
total  number  of  leucocytes,  without  regard  to  the  differential 
changes  involved,  does  not  of  necessity  constitute  a  leucocytosis. 

1  Wien.  klin.  Woch.,  1894,  vol.  vii.,  p.  71. 

2  Ibid.,  1895,  vol.  viii.,  p.  797. 

3  Bull,  of  the  Johns  Hopkins  Hosp.,  1897,  vol.  viii.,  p.  85. 
*  Am.  Joum.  of  Med.  Sciences,  1899,  vol.  cxvii.,  p.  139. 

5  Loc.  cit. 


PLATE  III, 


'^z 


Leucocytosis. 
(  Triacid  Stain.) 


The  blood  field  from  a  case  of  croupous  pneumonia.  The  leucocytes  are  all  of  the  polynuclear 
neutrophile  type.  The  erythrocytes  show  no  deformity,  and  stain  a  normal  orange 
color. 

Contrast  this  illustration  with  leukemia,  Plates  IV  and  V. 

(E.  F.  Faber,/^c.) 


PHYSIOLOGICAL    LEUCOCYTOSIS. 


177 


Nor  is  it  possible  to  recognize  the  condition  with  certainty  by  any 
such  criterion  as  a  deviation  from  the  ratio  of  red  to  white  cells 
maintained  in  health.  To  state  that  a  patient's  blood  contains, 
say,  50,000  leucocytes  to  the  cubic  millimeter  suggests  both  leu- 
cocytosis  and  leukemia,  but  to  add  to  such  a  statement  the  fact 
that  of  these  50,000  leucocytes  90  per  cent,  are  of  the  polynuclear 
neutrophile  variety  at  once  stamps  the  condition  as  a  genuine  leu- 
cocytosis.  In  order,  therefore,  to  distinguish  leucocytosis  with 
absolute  certainty  the  character  of  the  leucocytes  involved  in  the 
increase  must  be  determined  by  a  differential  count  of  the 
stained  specimen  of  blood.     (See  Plate  III.) 

Leucocytosis  may  be  of  a  more  or  less  transient  character,  or 
may  persist  for  a  long  period,  its  duration  being  dependent  upon 
the  nature  of  the  underlying  cause.  In  acute  diseases  it  is  usually 
a  temporary  condition,  but  in  long-continued  affections  it  is  pro- 
longed in  relation  to  the  chronicity  of  the  lesion  by  which  the 
increase  is  excited. 

For  clinical  purposes  all  forms  of  leucocytosis  may  be  classed 
under  two  main  groups,  physiological  and  pathological,  these  be- 
ing further  divided  as  follows  : 

PJiysiological  Leucocytosis, 

1 .  Leucocytosis  of  the  new-born. 

2.  Digestion  leucocytosis. 

3.  Leucocytosis  of  pregnancy  and  parturition. 

4.  Leucocytosis  due  to  thermal  and  mechanical  influences. 

5.  Terminal  leucocytosis. 

Pathological  Leucocytosis. 

1.  Inflammatory  and  infectious  leucocytosis. 

2.  Leucocytosis  of  malignant  disease. 

3.  Post-hemorrhagic  leucocytosis. 

4.  Toxic  leucocytosis. 

5.  Experimental  leucocytosis. 


PHYSIOLOGICAL  LEUCOCYTOSIS. 

The  leucocytoses  associated  with  a  number  of 

Character,    purely  physiological  conditions  are  generally  of 

brief  duration,  and  as  a  rule   involve  a  moderate 

increase  in  the  white  corpuscles,  the  gain  in  many  instances  being 

trifling  and  never  excessive.     As  noted  in  a  preceding  paragraph, 

12 


178  THE    LEUCOCYTES. 

the  increase  sometimes  affects  all  forms  of  leucocytes  equally,  so 
that,  although  the  total  number  of  cells  is  higher  than  the  normal 
standard,  the  relative  percentages  of  the  different  varieties  remain 
in  the  ratio  obser\^ed  in  normal  blood.  In  other  instances  the 
gain  is  due  to  an  absolute  and  relative  increase  in  the  polynuclear 
neutrophile  leucocytes,  with  a  consequent  decrease  in  the  per- 
centage of  non-granular,  mononuclear  forms. 

The  increase  of  leucocytes  under  such  condi- 
Causal         tions    is   to   be   regarded  usually  as  a  physical 
Factors.       phenomenon  depending  upon  temporary  concen- 
tration of  the  blood,  or  upon  an  unequal  distri- 
bution of  the  cells  in  favor  of  the  peripheral  vessels.      Evidence 
is  wholly  lacking  to  show  that  it  is  caused  by  an  actual  over-pro- 
duction of  leucocytes  by  the  blood-forming  organs,  thus  produc- 
ing a  general  increase  through  all    parts  of  the   body.     It   is, 
therefore,  reasonable  to  beheve  that  the  high  leucocyte  counts 
may  be  accounted   for  by   such  factors   as  decrease  in  the  total 
volume  of  blood  plasma,  and  the  transference  of  cells  from  the 
vessels  of  the  deeper  tissues  to  those  of  the  superficial  parts  of 
the  body. 

I .  Lcticocytosis  of  the  New-bom.  The  blood  of  the  infant  at 
birth  contains  two  or  three  times  the  number  of  leucocytes  found 
in  the  normal  adult,  the  count  usually  ranging  from  15,000  to 
20,000  or  higher  during  the  first  forty-eight  hours  of  hfe.  After 
this  time  the  number  of  cells  gradually  decreases  until,  by  the 
end  of  the  first  or  second  week,  it  has  fallen  to  an  average  of 
from  10,000  to  15,000,  which  figures  may  be  considered  normal 
for  children  under  one  year  of  age.  Gundobin  ^  has  determined, 
by  a  series  of  differential  counts,  that  the  increase  is  due  chiefly 
to  an  excessive  gain  in  the  polynuclear  neutrophiles,  the  propor- 
tion of  these  cells  during  the  first  ten  days  after  birth  averaging 
from  60  to  70  per  cent,  of  all  forms  of  leucocytes.  The  extent 
of  this  increase  becomes  apparent  when  one  recalls  the  fact  that 
in  the  infant  the  relative  proportion  of  these  cells  to  the  other 
varieties  is  usually  not  more  than  40  per  cent.  By  the  tenth  day 
this  polynuclear  increase  usually  subsides,  and  the  percentage  of 
mononuclear  forms  rises  to  the  figure  normal  at  this  period  of 
life.  (See  Section  VI.)  In  prematurely-born  infants  a  similar  in- 
crease in  the  number  of  leucocytes  is  present,  but  the  mononu- 
clear forms  rise  to  their  normal  percentage  more  rapidly  than  in 
the  full-term  baby ;  thus,  in  the  case  of  an  eight-months'  child, 
examined  by  Whitney  and  Wentworth,"  the  large  and  small  lym- 

ijahrb.  f.  Kinderheilk.,  1S93,  vol.  xxxv.,  p.  187. 

2Cited  by  Rotch  :   "Paediatrics,"  etc.,  Phila.,  1896,  p.  348. 


PHYSIOLOGICAL   LEUCOCYTOSIS.  I  79 

« 

phocytes,  which  averaged  together  but  26  per  cent,  at  birth,  rose 
to  80  per  cent,  by  the  fourth  day,  remaining  at  practically  this 
figure  through  subsequent  counts. 

The  leucocytosis  of  the  new-born  is  probably  attributable 
partly  to  concentration  of  the  blood  by  the  drain  on  the  body- 
fluids  incident  to  the  early  days  of  life,  and  partly  to  the  influence 
of  digestion  leucocytosis  which  is  especially  active  at  this  period. 

2.  Digestion  Leucocytosis.  Within  an  hour  after  taking  food 
an  appreciable  increase  in  the  number  of  leucocytes  may  be  ob- 
served in  the  great  majority  of  healthy  individuals,  the  count 
reaching  its  maximum  within  from  two  to  four  hours  after  the 
meal,  and  then  gradually  declining.  Rieder  ^  estimates  the  aver- 
age increase  at  about  33  per  cent,  in  excess  of  the  normal  figure. 
Meals  rich  in  albuminoids  are  followed  by  a  more  marked  increase 
than  those  consisting  chiefly  of  vegetable  articles  of  diet.  In  in- 
dividuals whose  process  of  digestion  is  slow  from  any  cause  the 
appearance  of  the  leucocytosis  is  also  delayed.  The  following  two 
instances,  taken  from  von  Limbeck,^  illustrate  the  development  of 
the  leucocytosis  in  the  normal  adult : 


Time. 

Count  of  Leucocytes. 

Time. 

Count  of  Leucocytes. 

II. 15  A.  M.3 

7,600 

11.30  A.  M.3 

5,800 

12.15  P-  M. 

6,000 

12.30  P.  M. 

10,600 

1. 15  P.  M. 

8,500 

1.30- P.  M. 

10,600 

3-15  P-  M. 

12,000 

2.30  P.  M. 

9,600 

5.15  P.  M. 

14,000 

3.30  P.  M. 

6,800 

7.15  P.  M. 

10,000 

6.00  P.  M. 

6,600 

The  gain  is  due  usually  to  a  predominance  of  polynu clear  neu- 
trophil forms,  with  a  consequent  relative  diminution  in  large  and 
small  lymphocytes  ;  but  in  some  instances  the  differential  count 
remains  normal,  all  forms  of  cells  sharing  equally  in  the  increase. 

Digestion  leucocytosis  is  not  invariably  present  even  in  those 
who  apparently  enjoy  perfect  health,  its  absence  in  such  instances 
remaining  entirely  unexplained.  It  is  also  absent  occasionally  in 
chronic  constipation,  frequently  in  chronic  gastric  catarrh,  and 
anemia,  and  is  found  in  only  a  small  proportion  of  cases  of  gastric 
carcinoma.  Other  lesions  of  the  gastro-intestinal  tract,  and  dis- 
eases characterized  by  high-grade  anemia  and  by  marked  de- 
bility may  greatly  delay  or  even  entirely  prevent  the  increase. 
Rieder  ^  is  authority  for  the  statement  that  digestion  leucocytosis 

1  **  Beitrage  zur  Kenntniss  der  Leukocytose, "  etc.,  Leipzig,  1892. 

2Loc.  cit. 

3  Meal  of  nitrogenous  and  farinaceous  food. 

4Loc.  cit. 


l80  THE   LEUCOCYTES. 

does  not  occur  during  pregnancy,  and  Bohland^  finds  that  it  fails 
to  develop  during  the  administration  of  tannic  acid. 

In  children,  especially  in  young  breast-fed  infants,  the  increase 
is  ver}'  decided  ;  in  the  new-born  counts  of  from  30,000  to  35,000 
may  follow  the  first  few  feedings.  (See  Section  VI.)  The  leucocy- 
tosis  is  also  marked  after  fasting,  and  in  diabetics. 

3 .  Leiicocytosis  of  Pregnancy  and  Parturition.  In  the  maj  ority  of 
primiparae  a  moderate  leucocytosis,  not  usualh*  involving  an  in- 
crease in  excess  of  double  the  normal  count,  is  obser\'ed  during 
the  later  months  of  pregnancy.  The  increase  is  less  constant 
and  much  less  marked  in  multiparae,  occurring  in  a  smaller  per- 
centage of  the  latter,  and  amounting  to  a  cellular  gain  of  about 
one-sixth  the  original  count  on  the  average.  The  maximum 
number  of  cells  is  usually  found  immediately  before  and  after  de- 
liver>^  at  which  time  the  number  of  leucocytes  commonly  rises 
to  about  15,000  per  cubic  millimeter.  During  convalescence 
the  leucocytosis  gradually  declines,  and  disappears  before  the 
end  of  the  first  week  after  deliver}^,  in  uncomplicated  cases. 
As  a  general  rule,  in  both  primiparae  and  in  multipara,  the  de- 
gree of  increase  is  more  decided  in  young  wom.en  than  in  those 
of  middle  ag-e.  It  is  also  marked  in  the  late  rather  than  in  the 
early  stages  of  gestation  and  of  labor. 

The  careful  blood  studies  by  Hibbard  and  White  ^  in  55  preg- 
nant women  (33  primiparae  and  22  multiparae)  furnish  the  most 
reliable  data  concerning  the  leucocytosis  of  this  condition.  These 
authors  found  that  leucocytosis  occurred  before  delivery  in  84 
per  cent,  of  primiparae  and  in  75  per  cent,  of  multiparae,  the  aver- 
age counts  in  32  of  the  former  being  15,021  (50  per  cent,  above 
normal)  and  in  20  of  the  latter  1 1,700  (17  per  cent,  above  nor- 
mal). In  uncompHcated  pregnancies  the  average  count  just  be- 
fore delivery  was  16,100  for  primiparae  and  1 1,800  for  multiparae. 
In  normal  labor  the  number  of  leucocytes  fell  rapidly  after  deliv- 
ery, gradually  reached  the  normal  standard  by  the  fourth  or  fifth 
day,  and  then  again  slowly  rose  until  the  seventh  day,  when  a 
decline  to  normal  was  again  obsen^ed. 

Differential  counts  in  19  cases  of  the  above  series  showed  that 
the  leucocytosis  was  of  the  polynuclear  neutrophile  type,  a 
marked  relative  and  absolute  increase  in  these  cells  being  con- 
stantly present ;  as  a  rule  their  percentage  was  from  85  to  95  of 
all  forms  of  leucocytes,  usually  being  higher,  the  higher  the  leu- 
cocytosis.    These  results  are  unlike  those  obtained  by  Rieder^ 

^Centralbl.  f.  inn.  Med.,  1899,  vol.  xx.,  p.  361. 
2Journ.  of  Exper.  Med.,  1898,  vol.  iii.,  p.  639. 
3  Loc.  cit. 


PHYSIOLOGICAL   LEUCOCYTOSIS.  l8l 

and  by  Bjorkman,^  the  former  having  stated  that  the  various 
forms  of  cells  remain  practically  normal,  while  the  latter  attrib- 
utes the  increase  to  a  predominance  of  mononuclear  elements. 

Lactation,  of  itself,  has  no  appreciable  effect  upon  the  leuco- 
cytes, so  that  a  leucocytosis  occurring  in  a  nursing  woman  should 
be  attributed  to  inflammatory  condition  of  the  breast  or  nipple — 
even  a  mild  mastitis  or  a  slight  irritation  of  the  nipple  being  cap- 
able of  causing  a  prompt  leucocytosis. 

The  number  of  leucocytes  is  somewhat  in  excess  of  normal 
for  a  few  days  preceding  and  during  menstruation  in  the  majority 
of  healthy  women,  according  to  the  investigations  of  Sfameni,^ 
but  the  increase  scarcely  ever  reaches  a  degree  which  may  be 
regarded  as  a  leucocytosis. 

4.  Leucocytosis  Due  to  Thermal  and  Mechanical  Influences.  A 
transient  increase  in  the  number  of  leucocytes  of  the  peripheral 
blood,  not  involving  a  disturbance  of  the  normal  ratio  between  the 
different  forms  of  cells,  is  produced  by  active  local  or  general 
h'msc2ilar  exercise  ;^  hy  hriti  Q^Y^osuYQ  to  atmospheric  cold  f'  by 
cold  baths,  either  local  or  general ;  ^  and  by  the  application  of 
electricity^  and  of  massage !"  The  number  of  leucocytes  is  also 
increased  by  the  effect  of  prolonged  dry  or  moist  heat.^ 

The  increase  under  these  circumstances  is  generally  attributed 
to  blood  concentration  due  to  the  influence  of  increased  vaso- 
motor tension,  whereby  the  liquid  elements  of  the  blood  are  tem- 
porarily decreased,  and,  in  addition,  many  of  the  cells  lodged  in 
the  deeper  tissues  of  the  body  are  swept  into  the  peripheral  cir- 
culation. As  a  rule,  all  varieties  of  leucocytes  share  equally  in 
the  process,  no  single  form  being  unduly  increased  at  the  ex- 
pense of  the  others. 

5.  Terminal  Leucocytosis.  Terminal  or  pre-agonal  leucocyto- 
sis is  the  term  applied  to  an  increase  in  the  number  of  leucocytes 
of  the  peripheral  circulation  frequently  observed  just  before  death. 
It  occurs  during  the  terminal  stages  of  a  number  of  different 
diseases,  and  is  especially  marked  in  those  conditions  in  which 
death  comes  slowly,  being  ushered  in  by  a  more  or  less  mori- 
bund state  of  the  patient  lasting  for  a  considerable  length  of  time. 
The  increase  is  usually  moderate,  and  the  counts  do  not  often 
exceed  20,000  or  30,000  per  cubic  millimeter,  except  in  those 

^  Am.  Medico- Surg.  Bull.,  1894,  vol.  vii.,  pp.  17  and  79, 
^Loc.  cit. 
3  Oliver  :  loc.  cit. 

*Wintemitz  :  Centralbl.  f.  klin.  Med.,  1893,  vol.  xiv.,  p.  1017.  Thayer:  Johns 
Hopkins  Hosp.  Bull.,  1893,  vol.  iv.,  p.  t,"}. 

5  Mitchell  :  Am.  Journ.  of  Med.  Sci.,  1894,  vol.  cvii.,  p.  502. 
^  Friedlander :  Congress  f.  inn.  Med.,  Berlin,  1897. 


I  82  THE    LEUCOCYTES. 

cases  in  which  decided  circulator}^  embarrassment  has  existed  for 
some  time.  Most  commonly  the  blood-picture  is  one  of  ordinar)^ 
polynuclear  neutrophile  leucocytosis,  although  occasionally  the 
large  and  small  lymphocytes  show  disproportionately  high  per- 
centages, and  still  more  rarely  all  forms  of  cells  may  be  increased 
equally. 

In  pernicious  anemia  the  increase  may  be  so  great  as  to  simu- 
late lymphatic  leukemia,  according  to  Cabot,^  who  found  the  fol- 
ing  blood  changes  on  the  day  of  death  in  this  disease  :  ratio  of 
white  to  red  corpuscles,  i  to  15  ;  differential  count  showed  91.7 
per  cent,  of  lymphocytes,  j .j  per  cent,  of  polynuclear  neutro- 
philes,  and  0.5  per  cent,  of  eosinophiles.  Four  megaloblasts  to 
one  thousand  leucocytes  were  also  found. 

The  following  data  were  obtained  by  the  writer  in  a  case  of 
pernicious  anemia  eighteen  hours  before  death :  hemoglobin, 
12  per  cent.;  erjthrocytes,  622,500  per  cb.  mm.;  leucocytes, 
18,600  per  cb.  mm.  The  differential  count  of  one  thousand 
white  corpuscles  showed  :  lymphocytes,  46.0  per  cent.;  polynu- 
clear neutrophiles,  49.7  per  cent.;  eosinophiles,  2.3  per  cent.; 
myelocytes,  1.6  per  cent,  and  basophiles,  0.4  per  cent.  Meg- 
aloblasts outnumbered  normoblasts  three  to  one,  twenty-four  of 
the  former  being  found  in  the  count  of  one  thousand  leucocytes. 
The  number  of  leucocytes  in  four  previous  counts  having  ranged 
from  1,000  to  2,400  per  cubic  millimeter,  and  the  proportion  of 
lymphocytes  from  42  to  48  per  cent.,  this  case  illustrates  the  oc- 
currence of  a  terminal  leucocytosis  without  a  notable  change  in 
the  relative  percentage  of  different  forms  peculiar  to  the  case  in 
question. 

The  principal  cause  of  this  form  of  leucocytosis  is  thought  to 
be  peripheral  stasis  dependent  upon  failure  of  circulator}^  com- 
pensation, but  in  many  instances  there  seems  to  be  good  reason 
to  believe  that  terminal  infections  also  act  as  the  causal  factors. 

PATHOLOGICAL  LEUCOCYTOSIS. 

Increase  in  the  number  of  leucocytes,  involving 
OccuRRENXE.  chiefly  the  polynuclear  neutrophile  cells  in  the 
great  majority  of  instances,  is  associated  with  a 
wide  variety  of  pathological  conditions,  mainly  inflammatoiy,  in- 
fectious, and  toxic  in  character,  and  in  such  conditions  the  under- 
lying cause  of  the  phenomenon  is  radically  different  from  that 
which  determines  the  increase  in  physiological  leucocytosis. 
Prominent  examples  of  pathological  lesions  in  which  leucoc}toses 

1  Loc.  cit. 


PATHOLOGICAL    LEUCOCYTOSIS.  1 83 

of  this  character  are  observed  are  pneumonia,  diphtheria,  scarlet 
fever,  erysipelas,  rheumatic  fever,  variola,  and  various  septic 
processes.  Enteric  fever,  Malta  fever,  the  malarial  fevers,  influ- 
enza, and  measles  are  notable  exceptions,  for  in  these  acute  in- 
fections leucocytosis  does  not  occur  except  as  the  result  of  some 
complication. 

The  extent  of  the  leucocytosis,  inasmuch  as  it 
Degree  of  depends  both  upon  the  nature  of  the  exciting  cause 
Increase.  and  upon  the  individual's  reactive  powers,  varies 
within  wide  limits  in  different  cases.  It  is  safe  to 
state,  however,  that  in  the  great  majority  of  instances  the  number  of 
leucocytes  is  rather  below  than  above  20,000  to  the  cubic  milli- 
meter, counts  in  excess  of  this  figure  being  noted  in  only  about 
one-fourth  of  the  cases  in  which  the  leucocytes  exceed  the  nor- 
mal limits  of  health.  A  count  of  25,000  cells  per  cubic  milli- 
meter may  be  regarded  as  a  decided  leucocytosis,  while  an  in- 
crease of  from  40,000  to  50,000  is  of  extremely  rare  occurrence. 
In  an  analysis  of  one  hundred  consecutive  counts  made  by  the 
writer  in  pathological  conditions,  in  which  the  number  of  leuco- 
cytes reached  or  exceeded  10,000  per  cubic  millimeter,  it  was 
determined  that  the  counts  were  below  20,000  in  65  per  cent,  of 
cases,  and  between  20,000  and  30,000  in  28  per  cent.;  in  4  per 
cent,  the  increase  was  between  30,000  and  40,000 ;  in  2  per 
cent,  between  40,000  and  50,000 ;  and  in  only  i  per  cent,  did  it 
exceed  50,000.  Judging  from  these  figures,  which,  it  should  be 
remembered,  are  applicable  only  to  the  average  case,  it  appears 
to  be  the  rule  that  in  most  leucocytoses  the  increase  amounts  to 
a  trifle  more  than  double  the  number  normal  in  health. 

With  rare  exceptions,  the  increase  affects  chiefly 
Differential  the    polynuclear  neutrophile   cells,  which   com- 
Changes.      monly  constitute  at  least  85  per  cent,  of  the  dif- 
ferent forms  of  leucocytes.     In  many  instances 
the  percentage  is  much  higher,  as,  for  example,  in  a  case  of  sup- 
purative meningitis,  reported  by  Stengel,^  in  which  a  differential 
count  showed  99.5  per  cent,  of  this  variety  of  cells.     The  excep- 
tional cases  in  which  these  disproportionately  high  percentages  of 
polynuclear  neutrophiles  are  sometimes  wanting  are  encountered 
in  the  leucocytoses  of  malignant  disease,  after  hemorrhage,  in  the 
moribund,  and  in  children.     The  relative  lymphocytosis  which  is 
occasionally  observed  under  these  circumstances  is  considered  in 
connection  with  these  conditions.     Coincident  with  the  increase 
in  polynuclear  forms,  there  is  a  marked  decrease  in  the  relative 
percentages  of  large  and  small  lymphocytes,  and  of  eosinophiles, 

1  Loc.  cit. 


^  r 


A 


184  THE    LEUCOCYTES. 

the  latter  variet}^  of  cells  sometimes  entirely  disappearing  from 
the  blood.  In  cases  in  which  the  increase  is  marked,  small  num- 
bers of  myelocytes  usually  may  be  observed,  together  with  an 
occasional  cell  whose  characteristics  at  once  suggest  a  stage  of 
development  intermediate  between  that  of  the  myelocyte  and  the 
t}^pical  polynuclear  neutrophile. 

The  exact  manner  in  which  pathological  leu- 

Causal        cocytosis  arises  is  a  question  about  which  many 

Factors.       conflicting  views  are  held  by  different  authorities, 

but  the  general  trend  of  opinion  at  the  present 
time  attributes  the  increase  chiefly  to  the  influence  of  chemotaxis. 
According  to  the  chemotactic  theor>^  of  leucocytosis,  the  pres- 
ence in  the  blood  of  certain  chemical  substances,  produced  by  in- 
fective principles,  is  capable  of  exerting  both  an  attractive  and  a 
repellent  influence  upon  the  ameboid  leucocytes.  If  the  collec- 
tions of  cells  are  attracted  by  such  substances  the  phenomenon  is 
known  as  positive  chemotaxis,  but  if,  on  the  other  hand,  they  are 
repelled,  the  condition  is  termed  negative  chemotaxis.  This  mass- 
ing and  repulsion  of  the  leucocytes  may  be  caused  by  various 
agents — by  thermal  and  mechanical  irritants,  by  bits  of  necrotic 
tissue  which  have  gained  entrance  to  the  circulation,  and  espe- 
cially by  the  presence  in  the  blood  of  bacteria,  or  of  their  meta- 
bolic products.  In  the  light  of  our  present  knowledge,  it  appears 
that  the  different  varieties  of  ameboid  leucocytes  respond  to  dif- 
ferent kinds  of  chemotactic  influences,  as  an  instance  of  which 
the  behavior  of  the  neutrophils  and  eosinophils  to  this  sort  of 
stimulus  may  be  cited.  Certain  substances,  which  for  one  of 
these  groups  of  cells  are  either  positively  or  negatively  chemo- 
tactic, are,  as  a  rule,  indifferent  to  the  other  group,  and  some- 
times even  antagonistic,  for  substances  which  serve  to  attract  one 
group  either  fail  to  influence  or  in  fact  repel  the  other.  Clin- 
ically, this  theory  seems  to  find  corroboration,  for  there  are  but 
few  exceptions  to  the  general  rule,  that  an  increase  in  either 
variety  of  these  cells  is  associated  with  a  constant  decrease  in 
the  other.  Ehrlich  ^  has  also  shown  that  the  mast  cells  are 
wholly  uninfluenced  by  those  substances  which  exert  a  strong 
chemotactic  influence  upon  the  neutrophiles  and  eosinophiles. 

The  intense  cellular  activity  excited  by  the  en- 
FuNXTioxs.     trance  of  bacteria  into  the  organism  indicates  an 

attempt  on  the  part  of  the  leucocytes  to  destroy 
the  invading  principle,  and  to  counteract  its  noxious  influences. 
In  this  endeavor  it  is  probable  that  in  a  restricted  sense  Metch- 
nikoff  s  hypothesis  holds  true,  and  that  the  immense  numbers  of 

'  Loc.  cit. 


PATHOLOGICAL    LEUCOCYTOSIS.  1 85 

phagocytic  leucocytes  which  crowd  the  blood  stream  mechan- 
ically engulf  and  destroy  many  of  the  invading  micro-organisms. 
But  of  still  greater  significance  is  the  faculty  which  the  leuco- 
cytes possess  of  producing  certain  chemical  substances  [alexines) 
acting  either  as  directly  bactericidal,  or  as  antitoxic  agents.  The 
researches  of  Buchner/  Lowy  and  Richter,^  Goldscheider  and 
Jacob,^  and  others  tend  to  show  that  such  substances  either  actu- 
ally destroy  the  infecting  micro-organisms,  or  at  least  antidote 
and  render  innocuous  their  poisonous  products.  This  joint  proc- 
ess of  phagocytosis  and  bactericidal  action  is  most  intensely  de- 
veloped at  the  period  of  maximum  leucocytosis,  according  to 
the  statements  of  Gabritschewsky.^ 

In  experimental   leucocytosis,  caused   by  the 
Hypoleucocy-  injection  of  such  irritants  as  bacteria  and  bacterial 
Tosis  AND  Hy-  products,  organic  extracts,  various  albumins,  and 
PERLEUCOCY-    evcn  by  simple  trauma,  it  has  been  found  that  the 
TOSIS.  first  effect  of  the  irritant  is  to  cause  a  rapid,  tran- 

sitory diminution  in  the  number  of  leucocytes  in 
the  peripheral  blood,  known  as  hypoleucocytosis,  this  decrease 
being  succeeded  in  turn  by  an  increase  of  these  cells  in  excess  of 
the  normal  standard,  termed  hyperleucocy tosis.  Frequently  in 
simple  traumatic  leucocytoses  after  the  disappearance  of  the  stage 
of  hyperleucocytosis,  the  duration  of  which  is  variable,  Sher- 
rington ^  was  able  to  distinguish  a  secondary  stage  of  hypoleuco- 
cytosis,  during  which  the  leucocyte  count  again  fell  below  the 
normal. 

Within  certain  limits,  the  extent  of  this  preliminary  decrease 
and  of  the  subsequent  increase  varies  directly  in  accordance 
with  the  intensity  of  the  irritant.  If  the  irritant  is  slight,  the  re- 
pellent influence  is  feeble,  and  the  consequent  cellular  increase 
is  inconspicuous — in  fact,  it  is  the  opinion  of  many  that  in  such 
instances  there  may  be  merely  a  local  accumulation  of  leucocytes 
at  the  site  of  the  injection,  without  any  real  increase  in  the  whole 
mass  of  cells.  If  the  effects  of  the  irritant  are  severe,  both  the 
repellent  and  the  attractive  stages  are  promptly  excited  and 
markedly  developed,  and  a  general  increase  in  the  number  of 
leucocytes  through  the  whole  circulatory  system  promptly  re- 
sults. If,  on  the  contrary,  the  effects  of  the  irritant  prove  to  be 
too  intense,  the  organism  suffers  a  depression  so  profound  that 

lArchiv.  f.  Hygeine,  1890,  vol.  xvii.,  p.  II2. 

2  Deut.   med.    Woch.,  1895,  vol.  xxix.,  p.   240.     Virchow's  Archiv.,  1898,  vol. 
cli.,  p.  220. 

^Zeitschr.  f.  klin.  Med.,  1894,  vol.  xxv.,  p.  373. 
•*  Central bl.  f.   Bakteriol.,  1898,  vol.  xxiii.,  p.  365. 
sProc.  of  the  Royal  Soc,  1893,  vol.  Iv.,  p.  161. 


1 86  '  THE    LEUCOCYTES. 

reaction  is  stifled,  and  leucocytosis  does  not  develop.  It  some- 
times happens  that  the  attractive  influences  of  the  chemotactic 
principle  predominate  over  its  repellent  action,  in  which  case  the 
stage  of  h}perleucocytosis  may  develop  without  the  initial  stage 
of  hypoleucocytosis.  Clinically,  the  preliminar}-  decrease  is  prac- 
tically never  observed,  perhaps  partly  for  the  reason  last  given, 
but  also  in  a  large  measure  because  the  repellent  action  of  the 
irritant  has  passed  off  by  the  time  the  disease  has  developed  into 
a  clinical  picture.  In  artificially  excited  leucocytoses,  however, 
its  appearance  is  quite  constant,  for  under  such  circumstances  the 
irritant  is  introduced  into  the  organism  suddenly  and  in  a  rela- 
tively massive  dose,  producing  a  more  or  less  decided  repellent 
influence. 

The  initial  stage  of  decrease  was  termed  the  leiicopenic  phase 
by  Lowit,^  who  attributed  the  change  to  an  actual  destruction  of 
the  leucocytes,  or  a  leiicocytolysis.  The  subsequent  increase  he 
spoke  of  as  the  Icucocytic  phase,  maintaining  that  for  the  produc- 
tion of  the  latter  the  preliminar}"  development  of  the  former  was 
in  some  unexplained  manner  essential.  The  work  of  Goldschei- 
der  and  Jacob "  definitely  proved  the  error  of  Lowit's  leucocyto- 
lytic  hypothesis,  and  demonstrated  the  fact  that  the  leucopenia 
was  dependent  purely  upon  an  altered  distribution  of  the  cells 
in  favor  of  the  vessels  of  the  deeper  circulation.  Extensive 
investigations  carried  on  by  these  authors  showed  that  at 
the  time  a  decided  diminution  occurred  in  the  number  of 
leucocytes  of  the  peripheral  blood,  there  was  a  simultane- 
ous increase  of  these  cells  in  the  capillaries  of  the  lungs  and 
other  internal  organs.  Furthermore,  it  was  also  shown  that  in 
some  instances  a  marked  leucocytosis  may  occur  without  the  ini- 
tial decrease,  this  being  the  case  after  the  injection  of  such  sub- 
stances as  the  glycerin  extract  of  spleen.  From  these  experi- 
ments it  seems  reasonable  to  attribute  the  initial  stage  of  decrease 
to  a  repellent  action  of  the  irritant,  and  to  infer  that  the  stage  of 
hyperleucocytosis  is  due  to  an  active  stimulation  of  the  hemo- 
genic  organs  which  results  certainly  in  an  increased  cellular 
output  from,  and  probably  in  an  increased  cellular  proliferation 
in,  this  situation.  Muir's  recent  investigations^  tend  to  strengthen 
this  belief,  and  to  throw  additional  light  on  the  phenomenon  of 
pathological  leucocytosis.  This  author  found  that  in  experimen- 
tal leucocytosis  in  animals,  produced  by  the  injection  of  patho- 
genic bacteria,  changes  occurred  in  the  bone  marrow,  consisting 

i*'Studien  z.  Physiol,  u.  Pathol,  d.  Blutes,"  Jena,  1892. 

2Loc.  cit. 

3  British  Med.  Journ.,  1898,  vol.   ii.,  p.  604. 


PATHOLOGICAL    LEUCOCYTOSIS.  I  8/ 

of  absorption  of  the  marrow  fat,  together  with  a  corresponding 
hyperplasia  of  the  cells  from  which  he  believes  the  leucocytes 
originate,  many  of  these  cells  undergoing  rapid  multiplication  by 
mitosis.  In  inflammatory  leucocytosis,  Muir  found  the  following 
suggestive  changes :  first,  a  local  increase  in  the  polynuclear  neu- 
trophile  cells  ;  second,  an  increase  of  the  same  variety  of  cells  in 
the  circulating  blood ;  and  third,  a  marked  increase  in  the  marrow 
of  their  direct  antecedents.  According  to  Ehrlich's  latest  views, ^ 
leucocytosis  involving  mainly  an  increase  of  the  polynuclear 
neutrophiles  (''polynuclear  neutrophile  leucocytosis")  is  the  ex- 
pression of  an  independent  chemotactic  reaction  on  the  part  of 
these  cells,  caused  by  the  remote  influence  of  dissolved  substances 
upon  the  bone  marrow,  whereby  this  tissue  throws  into  the  blood- 
current  excessive  numbers  of  these  elements. 

Schultz^  and  others,  on  the  contrary,  attribute  leucocytosis  en- 
tirely to  changes  in  the  distribution  of  the  cells,  maintaining  that 
increase  in  the  number  of  leucocytes  in  the  peripheral  vessels 
goes  hand  in  hand  with  a  decrease  in  their  number  in  the  vessels 
of  the  internal  organs,  and  vice  versa.  This  view,  however,  has 
been  shown  to  be  untenable. 

In  summing  up  the  various  experimental  and  clinical  data  bear- 
ing upon  the  nature  of  the  leucocytoses  associated  with  patho- 
logical conditions,  the  evidence  tends  to  confirm  the  view  that  the 
process  is,  in  all  instances,  save  perhaps  those  of  trivial  local  in- 
fections, a  general  one  throughout  the  entire  circulatory  system, 
and  that  it  is  symptomatic  of  an  excessive  output  and  rapid  de- 
velopment of  leucocytes  by  the  bone  marrow,  due  to  the  influence 
of  chemotactic  principles.  It  must  be  remembered  that  this  view 
is  in  part  based  upon  hypotheses,  but  it  nevertheless  represents 
the  belief  current  at  the  present  time. 

I.  hiflmnmatory  and  Infections  Leucocytosis.  In  this  class  are 
included  the  leucocytoses  occurring  during  the  course  of  a  num- 
ber of  diseases  of  inflammatory  and  infectious  character,  in  which 
the  increase  may  be  attributed  either  to  simple  inflammation,  or  to 
bacterial  infection,  or  to  both.  The  presence  of  such  a  leucocy- 
tosis is  to  be  regarded  as  symptomatic  of  an  attempt  on  the  part 
of  the  organism  to  overcome  the  noxious  invading  principle,  what- 
ever its  nature  may  be,  through  the  protective  action  of  the  white 
corpuscles.  Bearing  in  mind  this  construction  of  the  phenom- 
enon, it  is  possible  in  many  instances  to  derive  valuable  clinical 
information  from  the  presence  or  absence  of  a  cellular  in- 
crease. 

'  Loc.  cit. 

2Tagebl.  der  Naturforschervers  in  Heidelberg,  1889,  p.  405. 


I  88  THE    LEUCOCYTES. 

The  view  expressed  by  von  Limbeck/  that  the  height  of  the 
leucocytosis  is  dependent  upon  the  extent  of  the  inflammatoiy  ex- 
udate, is  not  tenable,  for  processes  characterized  by  insignificant 
exudates  are  capable  of  causing  as  great  an  increase  as  those  in 
which  this  outpouring  is  extensive.  As  a  rule,  leucocytoses  as- 
sociated with  purulent  exudates  are  much  more  marked  than 
those  due  to  serous  effusions.  The  essential  factor  in  determining 
the  degree  of  the  increase  is  not  the  extent  of  the  exudate,  nor, 
in  fact,  its  character,  but  rather  the  systemic  reaction  to  which  it 
gives  rise. 

The  degree  of  leucocytosis  may  be  considered  a  general  index 
to  the  intensity  of  the  infection,  and  to  the  strength  of  the  indi- 
vidual's resisting  powers  in  reacting  against  it.  It  follows, 
therefore,  that  intense  infections  occurring  in  individuals  whose 
resisting  powers  are  strong  produce  a  decided  increase ;  but 
the  presence  of  an  infection  of  like  intensity  in  one  whose  re- 
sisting powers  are  greatly  crippled  fails  to  cause  leucocytosis, 
for  in  such  an  instance  the  organism  is  so  overpowered  by  the 
effects  of  the  morbid  process  that  it  is  incapable  of  reacting. 
The  increase  is  either  absent  or  slight  when  a  trifling  infection 
is  associated  with  vigorous  resisting  powers,  and  moderate  when 
a  moderately  intense  infection  is  linked  to  fairly  well-developed 
resisting  powers. 

The  cHnical  inferences  to  be  drawn  from  these  facts  are  of 
value  chiefly  as  corroborative  of  other  well-known  physical 
signs,  but  are  obviously  untrustworthy  when  considered  apart 
from  the  latter.  A  marked  leucocytosis  indicates  simply  an  in- 
tense infection  in  a  person  whose  resisting  powers  are  normally 
developed  and  actively  exerted  against  the  disease,  but  it  is  of 
no  prognostic  value  in  itself,  for  it  conveys  no  idea  of  the  final 
outcome  of  the  conflict  between  the  disease  and  the  organism. 
Absence  of  leucocytosis,  or  a  slight  increase  may  be  either  of 
very  favorable  or  of  very  grave  significance,  inasmuch  as  these 
signs  occur  both  in  trivial  and  in  overwhelming  infections.  If 
the  absence  is  associated  with  clinical  manifestations  which  point 
to  a  severe  infection,  the  sign  may  be  depended  upon  as  being 
of  grave  prognosis. 

The  clinical  significance  of  the  leucocytoses  associated  with 
various  inflammatory  and  infectious  processes  will  be  discussed 
in  Section  VII.  A  more  or  less  decided  increase  in  the  num- 
ber of  leucocytes  occurs  with  great  constancy  in  the  following 
groups  of  diseases  of  this  nature  : 

^  Loc.  cit. 


PATHOLOGICAL    LEUCOCYTOSIS. 


189 


I.   General  Infectious  Diseases. 

Actinomycosis. 

Asiatic  cholera. 

Bubonic  plague. 

Cerebro -spinal  meningitis. 

Diphtheria. 

Dysentery. 

Erysipelas. 

Glanders. 

Malignant  endocarditis. 

Multiple  neuritis. 

Osteomyelitis. 

Pertussis. 


Pneumonia. 

Pyemia. 

Relapsing  fever. 

Rheumatic  fever. 

Scarlet  fever. 

Septicemia, 

Syphilis   (secondary), 

Trichiniasis. 

Vaccinia. 

Varicella. 

Variola. 

Yellow  fever. 


II.   Simple  and  Infective  Local  Inflanmiations . 


Acute  yellow  atrophy  of  the 

liver. 
Appendicitis,  catarrhal. 
Arthritis,  serous. 
Bronchitis,  acute. 
Cholangitis. 
Cholecystitis. 
Cystitis. 

Conjunctivitis,  acute. 
Dermatitis. 
Eczema. 
Endocarditis. 
Endometritis. 
Enteritis. 
Epididymitis. 
Gangrene : 

Appendicular. 

Cancrum  oris. 

Hepatic. 

Pancreatic. 

Pulmonary. 
Gastritis,  acute. 
Gastro-enteritis,  acute. 
Herpes  zoster. 
Infected  wounds. 
Mastitis. 
Meningitis. 
Nephritis,  acute. 
Orchitis. 
Otitis  media. 
Ovaritis. 
Pancreatitis. 


Pellagra. 

Pemphigus. 

Pericarditis. 

Peritonitis. 

Prurigo. 

Purulent  lesions : 

Appendicular  abscess. 

Cerebral  abscess. 

Hepatic  abscess. 

Ischio -rectal  abscess. 

Ovarian  abscess. 

Pancreatic  abscess. 

Pelvic  abscess. 

Perinephritic  abscess. 

Prostatic  abscess. 

Pulmonary  abscess. 

Retropharyngeal  abscess. 

Splenic  abscess. 

Superficial  abscess. 

Arthritis,  suppurative. 

Carbuncle. 

Empyema. 

Felon. 

Furuncle. 

Gonorrhea. 

Otitis  media,  suppurative. 

Phlebitis. 

Pyelonephritis. 

Pyonephrosis. 

Pyosalpinx. 

Quinsy. 
Splenitis. 


190 


THE    LEUCOCYTES. 


2.  Leticocytosis  of  Malignant  Disease.  A  moderate  leucocytosis 
is  commonly,  but  by  no  means  constantly,  associated  with  the  vari- 
ous forms  of  carcinomata  and  sarcomata,  but  the  cases  in  which  no 
increase  is  observed  are  even  more  numerous  than  those  in  which 
it  occurs.  It  is  more  common  and  the  increase  is  usually  re- 
garded as  more  marked  in  sarcoma  than  in  carcinoma,  but  in 
neither  condition  are  excessively  high  leucocytoses  met  with  fre- 
quently. In  the  writer's  experience,  the  increase,  when  it  does 
occur,  is  generally  moderate  in  most  forms  of  malignant  disease, 
counts  of  less  than  20,000  leucocytes  per  cubic  millimeter  being 
the  o-eneral  rule.  Cases  in  which  the  number  of  cells  exceeds 
this  figure  are  comparatively  rare,  but  are  distinctly  more  com- 
mon in  sarcoma  than  in  carcinoma ;  it  is  especially  in  rapidly 
growing  neoplasms  of  the  lung,  liver,  and  kidney  that  the  cells 
rise  to  30,000  or  40,000,  or  even  50,000  or  more.  In  a  series 
of  68  consecutiv^e  cases  of  malignant  disease  in  the  German  and 
Jefferson  hospitals  less  than  one-half  were  accompanied  by  a 
leucocyte  count  of  10,000  or  more,  this  figure  being  reached  or 
exceeded  in  approximately  45  per  cent,  of  cases  of  carcinoma, 
while  in  sarcoma  such  an  increase  was  noted  in  almost  65  per 
cent.  Five  per  cent,  of  all  cases  showed  a  high  leucocytosis, 
that  is,  counts  ranging  between  30,000  and  50,000.  (For 
further  data  concerning  the  leucocytosis  of  these  conditions,  see 
"  Malignant  Disease,"  Section  VII.) 

The  behavior  of  the  leucocytes  in  malignant  disease  appears 
less  contradictory  when  we  inquire  into  the  actual  influence  which 
these  growths  exert  in  provoking  leucocytosis.  It  is  the  cur- 
rent belief  that  malignant  disease,  per  se,  has  little  if  any  in- 
fluence of  this  sort,  and  that  the  increase,  if  any  occurs,  is  attribu- 
table to  local  inflammatory  complications  and  to  secondary  septic 
infections,  rather  than  to  the  specific  toxic  effects  of  the  neoplasm 
itself.  In  some  instances  it  is  reasonable  to  suppose  that  the 
profoundly  cachectic  state  of  the  patient  also  is  an  important  de- 
termining factor.  Clinically,  it  is  observed  that  tumors  of  rapid 
development,  involving  a  large  area  of  tissue  and  complicated  by 
extensive  metastases  cause  decided,  often  high,  leucocytoses  ;  while 
localized  tumors,  of  small  size  and  of  slow  growth,  give  rise  to 
trifling,  if  any,  increase.  Variations  from  this  general  rule  are 
the  result  of  differences  in  the  resisting  powers  of  different  indi- 
viduals, for  the  effects  of  this  factor  in  causing  leucocytosis  are 
potent  in  this,  as  in  other  pathological  conditions. 

Qualitatively,  the  leucocytes  usually  show  a  marked  absolute 
ancT relative  increase  in  the  polynuclear  neutrophiles,  with  a  con- 
sequent diminution  of  the  mononuclear  forms.      But  in  some  in- 


PATHOLOGICAL    LEUCOCYTOSIS.  I9I 

stances,  both  of  carcinoma  and  of  sarcoma,  the  polynuclear  forms 
are  relatively  below  the  normal  percentage,  and  the  lymphocytes 
increased,  so  that  the  blood  picture  is  not  one  of  leucocytosis,  but 
rather  one  of  relative  lymphocytosis ;  such  a  change  seems  es- 
pecially prone  to  occur  in  sarcoma  of  the  lymphatic  system,  in 
which  it  may  be  so  marked  that  it  suggests  lymphatic  leukemia. 
There  are  certain  cases  of  malignant  disease  in  which  the  propor- 
tion of  polynuclear  neutrophiles  rises,  although  the  total  number 
of  leucocytes  is  not  increased  ;  the  polynuclear  gain  is  less  than 
is  usually  found  with  high  leucocyte  counts,  but  it  is  sufficiently 
decided  to  be  regarded  as  of  the  same  significance  as  a  frank  leu- 
cocytosis involving  an  increase  in  the  total  number  of  cells. 

The  eosinophiles  are  variously  affected  in  different  cases ;  some- 
times they  are  greatly  diminished,  if  not,  indeed,  entirely  absent, 
as  in  most  leucocytoses  ;  sometimes  they  are  normal ;  and  some- 
times they  are  largely  increased  in  number.  The  increase  may 
be  pronounced  in  sarcoma,  this  being  due  probably  to  involve- 
ment of  the  bone  marrow  by  the  growth,  either  directly,  or  by 
metastasis. 

Small  numbers  of  myelocytes — .  5  to  i  or  2  per  cent. — are  ex- 
ceedingly common,  being  found  with  great  constancy  in  cases 
with  marked  cachexia,  especially  in  carcinoma. 

3.  Post'hemorrhagic  Leticocytosis .  A  leucocytosis  of  moderate 
grade  commonly  occurs  as  the  result  of  hemorrhage  due  to  trau- 
matism or  to  other  causes.  It  has  been  found  that  in  animals 
the  stage  of  increase  is  preceded  by  a  well-defined  leucopenia, 
which  develops  immediately  after  the  loss  of  blood.  This 
initial  leucopenia,  however,  has  not  yet  been  demonstrated 
in  man,  although  it  probably  occurs.  In  an  extensive  traumatic 
hemorrhage  the  increase  sometimes  may  be  recognized  in  the 
peripheral  blood  within  an  hour  after  the  accident,  but  usually  it 
is  not  distinguishable  until  after  the  lapse  of  a  longer  period — 
from  five  to  ten  hours,  as  nearly  as  can  be  ascertained.  In 
hemorrhage  accompanying  various  pathological  conditions,  such, 
for  example,  as  gastric  ulcer,  lung  tuberculosis,  or  uterine  dis- 
ease, the  appearance  of  the  leucocytosis  is  less  prompt  than  in 
hemorrhage  from  trauma.  The  maximum  increase  is  usually 
within  moderate  limits — approximately  two  or  three  times  the 
normal  standard.  The  injection  of  a  salt  solution  decidedly  aggra- 
vates the  leucocytosis.  As  an  illustration  of  the  degree  of  leuco- 
cytosis which  is  commonly  encountered,  Rieder^  noted  in  four 
cases  (hematemesis  from  gastric  ulcer,  fatal  hemophilia,  and 
uterine  hemorrhage)  an  average  count  of  22,625,  the   maximum 

1  Loc.  cit. 


192 


THE    LEUCOCYTES. 


being  32,600,  and  the  minimum,  15,100.  Inasmuch  as  the 
height  of  the  increase  is  thought  to  correspond  to  the  strength 
of  the  organism's  reaction  in  compensating  the  blood  loss,  it 
varies  in  different  cases.  In  two  individuals  of  equally  strong 
regenerative  powers  a  severe  hemorrhage  will  produce  a  greater 
leucocytosis  than  a  slight  one.  The  duration  of  the  increase  also 
varies  with  the  individual  case,  for  it  depends  upon  a  similar  fac- 
tor; but  in  the  majority  of  instances  it  does  not  last  for  more 
than  three  or  four  days,  according  to  the  investigations  of  Lyon.^ 
Leucocytoses  excited  by  traumatic  hemorrhage  are  prone  to 
persist  longer  than  those  due  to  other  causes,  and  the  long-per- 
sisting increases  which  are  sometimes  associated  with  other  path- 
ological lesions  should  be  attributed  to  factors  other  than  the 
actual  loss  of  blood.  In  an  instance  of  leucocytosis  following 
venesection,  Rieder  -  found  that  the  increase  persisted  for  twelve 
days.  Head  ^  found  that  in  dogs  the  leucocytosis  following  ex- 
tensive hemorrhage  lasted  for  at  least  seven  days. 

In  the  great  majorit}^  of  instances  the  qualitative  changes 
chiefly  involve  the  polynuclear  neutrophils,  which  are  greatly 
increased  at  the  expense  of  the  other  forms  of  cells,  but  in  an 
occasional  instance  it  will  be  found  that  the  mononuclear  varieties 
are  greatly  in  excess  of  their  normal  percentages,  so  that  a  lym- 
phocytosis is  observed.  ]\Iyeloc}i:es  may  also  be  found  in  con- 
siderable numbers  in  many  cases. 

4.  Toxic  Leucocytosis.  Typical  examples  of  toxic  leucocytosis 
are  found  in  poisoning  by  ptomaijies,  and  by  coal-gas,  in  both  of 
which  conditions  the  predominant  influence  of  a  toxic  agency  in 
producing  the  increase  is  self-evident.  For  the  same  reason  the 
leucocytoses  occurring  as  the  result  of  ether  narcosis,  and  in  co)i- 
viilsions  and  acute  delirium,  are  included  in  this  classification.  In 
certain  diseases,  notably  in  the  uric  acid  diathesis,  in  cholemia, 
and  in  uremia,  the  presence  in  the  blood  of  toxic  principles  is 
thought  to  be  the  underlying  factor  of  the  increase  ;  the  same 
probably  is  true  of  a  number  of  other  diseases,  which,  for  ob\ious 
reasons,  have  been  classed  with  the  infectious  and  inflammatory 
leucocytoses. 

The  effect  of  gas  poisoning  is  illustrated  by  the  blood  ex- 
amination of  a  patient  recently  admitted  to  the  German  Hospital, 
fatally  poisoned  by  illuminating-gas.  The  leucocytes  were  in- 
creased to  32,000  per  cubic  millimeter,  the  gain  being  due  to  an 
excessive  predominance  of  polynuclear  neutrophiles,  as  determined 

iVirchow's  Archiv.,  iS8i,  vol.  Ixxxiv.,  p.  207. 

2Loc.  cit. 

3Joum.  Am.  Med.  Assn.,  1901,  vol.  xxxvii.,  p.  501. 


PATHOLOGICAL    LEUCOCYTOSIS.  1 93 

by  the  following  differential  count :  small  lymphocytes,  3.5  per 
cent.;  large  lymphocytes,  2.5  per  cent.;  polynuclear  neutrophiles, 
92.0  per  cent.;  eosinophiles,  0.5  per  cent,  and  myelocytes,  1.5 
per  cent.  To  what  extent  this  increase  depended  upon  the  ac- 
tual toxic  effects  of  the  gas,  and  to  what  extent  it  was  attribu- 
table to  peripheral  stasis  (which  was  marked  in  this  patient),  is 
conjectural. 

The  leucocytosis  caused  by  ether  narcosis  has  been  exhaus- 
tively studied  by  von  Lerber,^  and  by  Chadbourne.^  The  inves- 
tigations of  von  Lerber  included  10 1  cases,  of  which  number  leu- 
cocytosis was  found  in  more  than  95  per  cent.,  the  increase  fre- 
quently amounting  to  two  or  three  times  the  original  count ;  in 
the  majority  of  instances,  the  maximum  count  was  observed  sev- 
eral hours  after  the  anesthesia  was  produced.  Chadbourne  has 
carefully  studied  21  cases,  all  of  which  showed  a  more  or  less 
decided  leucocytosis,  the  minimum  gain  being  6  per  cent.,  the 
maximum  73  per  cent.,  and  the  average  37.3  per  cent.  He 
found  that  the  leucocytosis  developed  more  rapidly  during  the 
early  part  of  the  etherization,  and  that  only  exceptionally  did  it 
persist  for  more  than  twenty -four  hours.  Differential  counts  in 
five  cases  showed  that  all  forms  of  cells  were  proportionately 
increased.  This  author  attributes  the  increase  to  the  irritating 
effects  of  the  ether  vapor  upon  the  mucous  membrane  of  the  re- 
spiratory tract.  Results  similar  to  the  above  also  have  been  ob- 
tained by  Ewing,^  and  by  Ames,*  in  the  experimental  etherization 
of  animals. 

The  leucocytosis  associated  with  acute  delirium  and  with  con- 
vulsive seizures,  due  to  a  variety  of  causes,  has  been  studied  in 
detail  by  Capps,^  and  by  Burrows.^  Under  such  circumstances  the 
increase  is  usually  marked,  and  the  height  of  the  count  in  a  gen- 
eral way  is  dependent  upon  the  severity  of  the  attack.  The 
polynuclear  neutrophiles  are  chiefly  concerned  in  the  increase, 
with  a  consequent  decline  in  the  proportion  of  mononuclear 
forms.  The  leucocytosis  of  this  class  of  diseases  is  discussed 
more  fully  in  Section  VII. 

5 .  Experimental  Leucocytosis.  Leucocytoses  not  differing  es- 
sentially from  those  associated  with  various  local  and  general 
infections,  may  be  caused  by  the  administration  of  many  drugs, 

'  "  Ueber  die  Einwirkung  der  Aethernarkose  auf  Blut  u.  Urin.,"  Inaug.  Diss.  Ber- 
lin, 1896, 

i^Phila.  Med.  Jour.,  1899,  vol.  iii.,  p.  390. 
3N.  Y.  Med.  Journ.,  1895,  vol.  Ixi.,  p.  257. 
*Journ.  Am,  Med.  Assn.,  1897,  vol.  xxix.,  p.  472. 

5  Am.  Journ.  of  Med.  Sciences,  1896,  vol.  cxl.,  p.  650. 

6  Ibid. ,  1899,  "^o^-  cxvii.,  p.  503. 

13 


194 


THE    LEUCOCYTES. 


chemicals,  organic  principles,  bacteria,  bacterial  proteins,  and  by 
the  application  of  intense  irritants  and  revulsives  to  the  surface  of 
the  body.  No  doubt,  many  of  these  leucocytoses  should  be 
classed  either  as  inflammatory^  or  as  toxic,  owing  to  the  character 
of  their  exciting  causes,  but  for  the  sake  of  convenience  they  may 
be  grouped  under  this  heading. 

Leucocytoses  resulting  from  the  administration,  subcutaneously 
and  by  the  mouth,  of  various  drugs  and  other  substances  have 
been  studied  chiefly  by  the  Continental  investigators,  to  whom  we 
are  indebted  for  most  of  our  present  knowledge  of  this  subject. 
The  manner  in  which  such  agencies  act  in  causing  the  increase  is 
not  at  all  clear  in  many  instances,  but,  as  a  rule,  the  change  is 
thought  to  be  dependent  upon  chemotactic  influences,  as  in  in- 
flammatory and  infectious  leucocytoses,  as  w^ell  as  upon  concen- 
tration of  the  blood  from  vasomotor  changes. 

Lowit  ^  determined  that  a  preliminary  leucopenia  succeeded  by 
a  more  or  less  decided  leucocytosis  followed  the  subcutaneous  in- 
jection of  the  following  substances  :  hemialbtiinose,  pepsin,  nuclein, 
nucleic  acid,  curare,  leech  extract,  tuberculin,  filtered  yeast-cultures, 
pyocya7iin,  sodium  urate,  and  uric  acid.  This  change  was  not  ob- 
served, however,  after  the  injection  of  urea. 

Goldscheider  and  Jacob,^  conducting  a  large  number  of  experi- 
ments with  various  organic  animal  extracts,  obtained  results  simi- 
lar to  Lowit's  from  the  injection  of  the  extracts  of  spleen,  thymus, 
and  bo7te  marrow,  but  found  negative  results  from  the  use  of  the 
extracts  of  thyroid,  pancreas,  and  liver. 

Winternitz  ^  studied  the  effects  resulting  from  the  subcutaneous 
injection  of  substances  causing  both  transient  inflammatory  edema, 
and  aseptic  abscess  formation  at  the  site  of  the  injection.  In  the 
former  class,  which  includes  neutral  salts,  and  dihite  acids  and 
alkalies,  an  increase  in  the  number  of  leucocytes,  amounting  to 
from  40  to  75  per  cent,  of  the  original  count,  was  noted  ;  and  it 
was  furthermore  found  that  even  although  a  local  necrosis  was 
produced,  as  by  the  injection,  for  example,  of  a  solution  of  silver 
nitrate,  the  increase  still  did  not  become  excessive.  In  the  second 
class  of  more  active  irritants  which  produced  local  abscesses — tur- 
pentine, oil  of  mustard,  carbolic  acid,  croton  oil,  sapotoxin,  digitoxin, 
silver  futrate,  cupric  sulphate,  and  salts  of  mcirujy  and  of  antimo7iy 
— the  leucocytosis  was  much  more  decided,  and  of  less  transient 
duration.  As  a  rule,  in  these  experiments  the  height  of  the  leucocy- 
tosis ran  parallel  to  the  intensity  of  the  local  irritation  provoked. 

1  Loc.  cit. 
2Loc.  cit. 
3Archiv.  f.  exp,  Pathol,  u.  Pharmak.,  1895,  vol,  xxxv.,  p.  77. 


PATHOLOGICAL    LEUCOCYTOSIS.  I95 

Pohl  ^  noted  a  moderate  leucocytosis  following  both  the  inges- 
tion and  the  injection  of  absinthe,  acetic  ether,  extract  of  gentian, 
peppermint,  piperine,  the  oils  of  anise  and  fennel,  egg-albumin, 
and  sodium  albuminate.  With  the  last  two  substances  he  deter- 
mined that  the  increase  was  greater  when  they  were  given  by  the 
mouth  than  when  administered  subcutaneously  ;  the  gain  usually 
ranged  from  about  5  to  50  per  cent,  of  the  normal  count.  This 
investigator  also  found  that  quinine,  caffeine,  calomel,  sodium  bicar- 
'  bonate,  ethyl  alcohol,  and  hydrochloric  acid  did  not  cause  a  leucocy- 
tosis, while  bismuth  subnitrate  and  oxide  of  ii-on  produced  irregular 
results.  Many  of  the  above  experiments  have  been  substantiated 
by  the  later  work  of  von  Limbeck.^ 

Wilkinson^  observed  leucocytosis,  preceded  by  leucopenia, 
after  the  injection  oi potassium  iodide,  camphor,  quinine,  antipyrin, 
salicine,  salicylic  acid,  nuclein,  and  pilocarpine ;  by  the  repeated 
administration  of  the  latter  drug,  it  was  found  that  the  granules 
of  the  polynuclear  neutrophiles  disappeared,  although  no  effect 
was  produced  upon  the  granules  of  the  eosinophile  cells.  Von 
Jaksch"*  also  studied  the  effects  of  the  injection  oi pilocarpine,  and 
of  the  administration  by  the  mouth  of  nuclein,  and  found  that  by 
either  procedure  a  temporary  and  sometimes  very  marked  leu- 
cocytosis may  be  produced.  The  leucocytosis  caused  by  the 
ingestion  of  salicylic  acid,  according  to  Schreiber  and  Zandy,^ 
gradually  disappears  after  the  drug  has  been  given  for  a  few 
days. 

The  effects  of  the  ingestion  of  the  essential  oils  of  peppermint, 
turpentine,  and  cinnamon  have  been  studied  by  Meyer,^  while 
Hirt^  has  investigated  the  influences  of  the  simple  bitters  and 
drugs  such  as  the  tincture  of  myrrh.  Such  drugs  were  found  to 
cause  a  moderate,  but  easily  recognized  leucocytosis.  Krausman,^ 
by  the  injection  of  spermin,  and  of  protalbumose ,  and  Besredka,^ 
by  a  similar  use  of  carmine  and  of  arse?nc  trisidphate,  have  ob- 
tained varying  degrees  of  increase  in  the  number  of  leucocytes. 
A  marked  increase  is  produced,  according  to  Bohland  ^°  by  the 
injection  of  morphine,  Dover' s  powder,  sodium  salicylate,  pilocar- 
pine, antipyrin,  phenacetin,  and  antifebrin. 

^Archiv.  f.  exp.  Pathol,  u.  Pharmak.,  1889,  vol.  xxv.,  p.  51. 

2Loc.  cit. 

'British  Med.  Journ.,  1896,  vol.  ii.,  p.  836. 

^Centralbl.  f.  klin.  Med.,  1892,  vol.  xiii.,  p.  81, 

^Deut.  Arch.  f.  klin.   Med.,  1899,  vol.  Ixii.,  p.  242. 

^  Cited  by  von  Limbeck,  loc.  cit. 

7  Ibid. 

8  These  de  St.  Petersbourg,  1898. 

'^Annal.  de  I'lnstitut  Pasteur,  1899,  ^ol-  xiii.,  p.  49. 
'"Centralbl.  f.  inn.  Med.,  1899,  vol.  xx,,  p.  361. 


196  THE    LEUCOCYTES. 

In  addition  to  the  substances  already  mentioned,  the  leucocy- 

tosis-producing  effect  oi  wdinous  purgative  drugs, ^  of  the  tra7isfusion 

of  blood  and  of  normal  salt  sohuion^  of  the  subcutaneous  use  of 

fibrin  ferment^  oi  hemoglobin,^  and  of  bacterial  cnlttires,^  extracts,^ 

and  protei7is  ^  has  also  been  demonstrated. 

Thymectomy  in  animals  is  followed  by  a  well-marked  leuco- 
cytosis,  associated  with  an  increase  in  the  bactericidal  properties 
of  the  blood. 

IV.     LYMPHOCYTOSIS. 

An  increase,  whether  relative  or  absolute,  in  the  lymphocytes 
above  the  number  normal  in  health  is  known  as  lymphocytosis. 
Relative  lymphocytosis  involves  simply  a  gain  in  the  percentage 
of  lymphocytes  without  a  coincident  increase  in  the  total  leucocyte 
count.  Absolute  lymphocytosis,  on  the  other  hand,  is  character- 
ized by  an  increase  above  normal  both  in  the  percentage  of  lympho- 
cytes and  in  the  total  number  of  leucocytes.  Barring  lymphatic 
leukemia,  in  which  the  lymphocytes  are  both  relatively  and  abso- 
lutely in  excess,  lymphocytosis  is  almost  always  a  relative  condi- 
tion, or  at  least  it  is  not  accompanied  by  a  decided  rise  in  the 
total  leucocyte  count. 

The  increase  in  the  proportion  of  lymphocytes  is  moderate  in 
most  instances,  the  greater  number  of  differential  counts  showing 
percentages  of  these  cells  ranging  from  50  to  70,  in  comparison 
with  the  maximum  normal  percentage,  about  30.  These  figures, 
of  course,  refer  to  the  blood  of  adults,  for  in  children  the  increase 
is  generally  greater,  owing  to  the  higher  proportion  of  lympho- 
cytes normally  found  at  this  period  of  life.  A  differential  count 
which  shows,  for  instance,  60  per  cent,  of  lymphocytes  means  a 
decided  lymphocytosis  in  the  adult,  but  is  entirely  within  the 
normal  limits  in  the  young  infant.  Either  type  of  cells,  large  or 
small,  may  predominate,  or  the  change  may  not  involve  any  con- 
spicuous deviation  from  the  normal  ratio  of  one  form  to  the  other. 
Frequently  it  happens  that  the  two  varieties  possess  such  similar 
characteristics  that  it  is  impossible  to  determine  which  prevails. 
Occasionally  the  lymphocytosis  depends  largely  upon  unusually 
large  percentages  of  the  so-called  "transitional"  forms. 

Lymphocytosis  may  be  due  either  to  changes  in  the  distribu- 
tion of  the  cells  through  the  circulatory  system,  or  to  their  in-  . 

1  De  Rienzi  and  Boeni  :  Gaz.  degli  Osp.  e.  d.  Clin.,  1898,  vol.  xix.,  p.  1570. 
2 Hand:  N.  Y.  Med.  Journ.,  1900,  vol.  Ixxi.,  p.  556. 
3Birk  :  "Das  Fibrin-Ferment  im  lebenden  Organismus,"  Dorpat,  1880. 
*Bojanus:  "Exp.  Beitrage  z.  Physiol,  u.  Pathol,  d.  Blutes,"  Dorpat,  1S81. 
5  Hankin  and  Kanthack  :   "  Proc.  Cambridge  Philosoph.  Soc,"  Jan.,  1892. 
^  Buchner :  Arch.  f.  Hygiene,  1890,  vol.  x. ,  p.  84. 


LYMPHOCYTOSIS.  igy 

creased  production  and  output  by  the  lymphatic  tissues.  Ehr- 
lich^  attributes  lymphocytosis  to  the  local  irritation  of  certain 
areas  of  lymphatic  glands  which  produces  an  increased  circulatory 
activity  in  these  situations,  in  consequence  of  which  large  numbers 
of  lymph  elements  are  swept  mechanically  from  the  lymphatics, 
and  enter  the  general  circulation.  He  does  not  regard  the  change 
as  an  expression  of  an  active  chemotactic  reaction,  to  which  the 
lymphocytes  are  insensible.  It  also  appears  reasonable  to  pre- 
sume that  the  lymphocytosis  which  often  accompanies  leucopenia 
may  be  traced  to  still  another  factor,  that  of  negative  chemotaxis, 
which  diminishes  the  number  of  polynuclear  neutrophiles,  and 
thus  brings  about  a  relative  increase  in  the  lymphatic  elements, 
upon  which  the  repellent  action  is  not  exerted. 

Lymphocytosis  has  been  observed  in  a  number  of  pathological 
conditions,  but  its  presence  may  be  considered  physiological  in 
but  a  single  instance — in  the  blood  of  infants  and  young  children ^ 
in  whom  such  a  change  is  entirely  normal.  This  tendency  to- 
ward a  lymphocytic  increase  in  infantile  life,  which  becomes  less 
notable  as  the  child  matures,  is  prone  to  become  markedly  exag- 
gerated in  many  of  the  forms  of  secondary  anemia  from  which 
children  suffer,  especially  the  anemias  secondary  to  syphilis,  tuber- 
culosis, rachitis,  gastro-enteritis,  and  scurvy  ;  less  commonly,  it 
has  been  observed  in  the  acute  infections. 

Lactation,  conditions  of  cachexia,  and  great  debility  in  the 
adult  are  in  many  instances  accompanied  by  abnormally  high  per- 
centages of  lymphocytes  in  the  blood.  It  is  a  well-known  fact 
that  differential  counts  show  a  higher  percentage  of  mononuclear 
non-granular  elements  in  the  blood  of  the  enfeebled  and  poorly- 
nourished  than  in  that  of  the  active  and  vigorous  individual. 

Similar  changes  are  frequently  associated  with  the  terminal 
stages  of  a  number  of  diseases,  and  maybe  found  after  hemorrhage 
from  various  causes — trauma,  hemophilia,  and  purpura. 

Lymphocytosis,  sometimes  decidedly  marked,  is  common  in 
certain  of  the  severe  anejnias,  especially  in  chlorosis,  pernicious 
anemia,  and  in  syphilitic  and  tuberculous  secondary  anemias  ;  it 
may  be  observed  during  the  course  of  a  few  of  the  acute  infectiojis, 
such  as  enteric  fever,  malarial  fever,  Malta  fever,  scarlet  fever, 
measles,  pertussis,  variola,  pulmonary  tuberculosis,  and  pneu- 
monia. 

Diseases  involving  the  spleen  and  lymphatic  glands  are  often  the 
cause  of  a  varying  degree  of  increase  in  the  lymphocytes,  common 
examples  of  such  conditions  being  chronic  malarial  splenic  tumors  ; 
simple,  syphilitic,  and  tuberculous  adenitis  ;  and  malignant  neo- 

^Loc.  cit. 


198  THE    LEUCOCYTES. 

plasms,  especially  sarcoma,  of  the  lymph  glands.     Enlai-gement  of 
the  tliyroid  gland  also  may  give  rise  to  a  similar  blood  picture. 

Distinct  lymphocytosis  has  been  observed  by  Wilkinson  ^  after 
the  injection  o{  qinnine  Jiydi'ochlorate  ;  and  by  Perry-  as  the  re- 
sult of  administration  of  thyroid  extract.  It  also  follows  the  in- 
jection of  tiibercidin,  and  pilocarpine. 

From  a  clinical  viewpoint,  lymphocytosis  is  of  value  chiefly  in 
the  diagnosis  of  lymphatic  letikenda.  Marked  absolute  increase 
in  the  number  of  lymphocytes  associated  with  enlargement  of 
the  lymphatic  glands  forms  a  pathognomonic  picture  of  this 
disease. 

The  recognition  of  a  doubtful  case  of  syphilis  may  be  facilitated 
by  the  occurrence  of  lymphocytosis  plus  eosinophilia. 

V.     EOSINOPHILIA. 

The  term  eosinophilia  is  used  to  denote  an  increase  above  the 
normal  standard  in  the  number  of  eosinophiles  in  the  circulating 
blood,  this  change  usually,  but  not  necessarily,  being  associated 
with  a  coincident  increase  in  the  relative  percentage  of  these  cells 
to  the  other  forms  of  leucocytes.  Thus  interpreted,  eosinophiha 
is  a  condition  of  absolute  increase,  in  contradistinction  to  a  purely 
relative  gain  in  percentage,  to  which  the  term  is  not  strictly  appli- 
cable. 

For  the  sake  of  uniformity,  it  is  customar}^  to  speak  of  the  per- 
centage of  eosinophiles  rather  than  of  their  actual  number,  but 
in  order  to  determine  accurately  the  presence  or  absence  of 
eosinophilia,  it  is  also  essential  in  every  instance  to  calculate  the 
number  of  eosinophiles  to  the  cubic  millimeter  of  blood,  from  data 
obtained  by  a  numerical  estimate  and  a  differential  count  of  the 
leucocytes,  thus  : 

Total  7itwiber  of      Percentage  of  eosinophiles  to       Total  niintber  of 
leucocytes        x  other  forms  of  =      eosifiophilcs 

per  cb.  mm.  leucocytes.  per  cb.  mm. 

The  necessity  for  such  a  calculation  is  forcibly  illustrated  in 
spleno-medullary  leukemia,  since  in  this  condition  the  relative 
percentage  of  eosinophiles  is  often  well  within  the  normal  limits, 
and  yet  a  striking  degree  of  eosinophilia  may  exist.  For  example, 
in  a  given  case  of  this  form  of  leukemia,  the  blood  count  shows 
300,000    leucocytes   per   cubic   millimeter  with    5    per  cent,   of 

^  Loc.   cit. 

^N.  Y.  Med.  Record,  1896,  vol.  1.,  p.  289. 


EOSINOPHILIA.  199 

eosinophiles.  This  percentage,  interpreted  into  the  actual  7iuinber 
of  cells,  means  an  eosinophilia  of  15,000  per  cubic  millimeter,  or 
an  increase  of  thirty-fold  in  excess  of  the  highest  normal  figure. 
It  is  also  true  that  a  high  percentage  of  eosinophiles  does  not  neces- 
sarily imply  eosinophilia,  for  a  differential  count  showing,  for  ex- 
ample, 10  per  cent,  of  these  cells,  with  a  total  leucocyte  count  of 
5,000  per  cubic  millimeter,  means  500  eosinophiles  to  the  cubic 
millimeter,  a  count  not  exceeding  normal. 

On  the  basis  of  a  variation  in  the  normal  number  of  leucocytes 
of  from  5,000  to  10,000  per  cubic  millimeter,  the  absolute  num- 
ber of  eosinophiles  may  range  from  25  to  500  per  cubic  millime- 
ter in  the  blood  of  the  healthy  adult.  An  increase  in  excess  of 
this  maximum  standard,  regardless  of  the  percentage  indicated  by 
the  differential  county  constitutes  eosinophilia. 

Granting  the  accuracy  of  the  current  view  that  the  hemic 
eosinophiles  are  purely  myelogenous  elements,  their  increase  in 
the  blood  may  be  attributed  to  the  influence  of  chemotaxis,  prob- 
ably of  a  specific  and  selective  character.  Under  the  influence  of 
such  a  stimulus  the  eosinophiles  are  attracted  from,  and,  perhaps, 
overproduced  by,  the  bone  marrow,  and  are  thrown  into  the  gen- 
eral circulation  in  large  numbers.  It  is  also  possible  that  to  a 
slight  extent  their  proliferation  from  Hke  cells  may  occur  in  the 
blood-stream  as  well. 

Increase  in  the  number  of  eosinophiles  occurs  as  a  physiolog- 
ical change  m.  young  infants^  in  women  during  the  menstrual  period, 
and  after  coitus.  With  these  three  exceptions,  the  presence  of 
eosinophilia  is  always  to  be  regarded  as  an  evidence  of  some 
pathological  condition. 

Once  believed  to  be  a  pathognomonic  sign  of  leukemia,  in  the 
light  of  more  recent  investigations  eosinophilia  is  now  known  to 
be  associated  with  diseases  of  almost  every  conceivable  nature ; 
in  fact,  it  has  been  reported  in  such  a  large  number  of  conditions 
of  such  widely  dissimilar  pathogenesis  that  its  value  as  a  clinical 
sign  must  be  largely  restricted.  Inasmuch  as  many  of  these  re- 
ported instances  of  eosinophile  increase  lack  verification,  it  can 
only  prove  confusing  to  give  here  a  list  of  the  many  pathological 
states  in  which  the  change  is  reputed  to  have  been  observed. 
The  following  list,  based  upon  the  work  of  Cannon,^  Zappert,^ 
Gollasch,^  T.  R.  Brown,^  von  Noorden,^  and  others,  includes  only 

^  Deut.  med.  Woch.,  1892,  vol.  xviii.,  p.  206. 

^Zeitschr.  f.  klin.  Med.,  1893,  vol.  xxiii.,  p.  227.  Also  Wien.  klin.  Woch., 
1892,  vol.  v.,  p.  347. 

3Forschr.  d,  Med.,  1889,  vol.  vii.,  p.  361. 

*Bull.  of  the  Johns  Hopkins  Hosp.,  1897,  vol.  viii.,  p.  79. 

^Zeitschr.  f.  klin.  Med.,  1892,  vol.  xx.,  p.  98. 


200  THE    LEUCOCYTES. 

those  diseases  in  which  eosinophilia  is  observed  with  a  great  de- 
gree of  constancy.     Such  conditions  are  : — 

I.  Diseases  of  the  Skin. 

Dermatitis  herpetiformis. 

Eczema. 

Leprosy. 

Lupus. 

Pellagra. 

Pemphigus. 

Prurigo. 

Psoriasis. 

Scleroderma. 

Urticaria. 

II.  Helminthiasis^ 

Ankylostomiasis. 

Ascaris  lumbricoides  infection. 

Oxyuris  vermicularis  infection. 

Tenia  mediocanellata  infection. 

Trichiniasis. 

III.  Diseases  of  the  Bones. 

Hypertrophy. 
Osteomalacia. 
Malignant  neoplasms. 

IV.  Postfebrile. 

Malarial  fever. 
Pneumonia. 
Rheumatic  fever. 
Scarlet  fever. 
Septicemia. 

V.  Bronchial  Asthma. 

VI.  Splcno-medullary  Leukemia. 

In  addition  to  the  conditions  listed  above,  eosinophilia  also 
occurs,  but  with  less  constancy,  in  some  forms  of  the  high-grade 
secondary  aiiemia  of  childhood,  in  purpura,  in  hemorrhagic  effusiojis, 
in  gofiorrhea,  in  syphilis,  in  malig?iant  disease,  and  in  fibrinoiis 
bro7tchitis.  It  is  also  seen  in  many  cases  of  splenomegaly,  and 
after  sple7iectomy,  its  development  under  the  latter  circumstance 


EOSINOPHILIA.  201 

being  regarded  as  a  compensatory  condition.  An  increase  in  the 
percentage  of  eosinophiles  has  also  been  noted  in  conditions  of 
starvation.  In  scarlet  fever  the  eosinophiles  usually  persist,  in 
spite  of  the  coexisting  polynuclear  leucocytosis,  and  the  same 
peculiarity  may  often  be  found  in  trichiniasis . 

Eosinophilia  may  be  produced  experimentally  by  the  injection 
of  a  number  of  medicaments,  such  as  antipyrin,  camphor^  nu- 
clein,  phosphorus,  pilocarpine,  tuberculin,  and  many  of  the  iron 
salts. 

Neusser  ^  and  his  school  have  contended  that  eosinophilia  is 
symptomatic  of  an  extensive  group  of  diseases,  chiefly  those  in- 
volving the  sympathetic  nervous  systejn,  the  sexual  organs,  and  a 
long  list  of  disorders  which  they  attribute  to  the  *'  xanthin  dia- 
thesis'' Most  of  these  views  have  been  unsubstantiated,  many 
are  misleading,  and  a  few  can  be  shown  to  be  fanciful.  Those 
who  are  inclined  to  investigate  some  of  the  remarkable  claims 
made  by  Neusser  as  to  the  diagnostic  and  prognostic  value  of 
eosinophilia  are  referred  to  his  original  communication  on  the 
subject. 

Diminution  in  the  number  of  eosinophiles  occurs  as  a  physiolog- 
ical process  during  digestioft,  and  after  active  fnusctdar  exercise. 
It  is  observed  usually  in  lymphatic  letikemia,  during  the  febrile 
stages  of  diphtheria,  influenza,  pneumonia,  enteric  fever,  and  septi- 
cemia, frequently  after  hemorrhage,  and  in  the  terminal  stages  of 
many  diseases.  The  number  of  eosinophiles  is  said  to  be  dimin- 
ished after  castration.  The  writer  has  found  a  decrease  or  even 
absence  of  eosinophiles  in  the  majority  of  cases  of  chlorosis 
and  per?iicious  anemia. 

The  chief  clinical  value  attached  to  eosinophilia  relates  to  its 
presence  in  trichiniasis,  in  which  infection  it  has  been  shown  to  be 
a  sign  of  great  reliability.  It  may,  however,  fail  to  develop  in 
this  condition. 

In  the  diagnosis  of  an  exanthema  which  is  suggestive  of  either 
scarlet  fever  or  of  measles,  eosinophilia  points  to  the  former  dis- 
ease, for  it  does  not  occur  in  the  latter. 

The  association  of  eosinophilia  and  lymphocytosis  constitutes  a 
blood  change  which  may  be  helpful  in  the  recognition  of  an  ob- 
scure case  of  syphilis. 

High  percentages  of  eosinophiles  in  chlorosis,  in  pernicious 
anemia,  and  after  hemorrhage  are  generally  regarded  as  an  evi- 
dence of  good  regenerative  powers  of  the  hemogenic  organs,  and 
are  therefore  of  favorable  import.      (Rieder.^) 

^Wien.  klin.  Woch.,   1894,  vol.  vii.,  p.  737. 
2Loc.  cit. 


202  THE    LEUCOCYTES. 


VI.     BASOPHILIA. 


Increase  in  the  number  of  basophiles  in  the  circulating  blood 
is  of  rare  occurrence,  having  been  observed  in  but  few  diseases 
except  the  spleno-medullary  variety  of  leukemia,  in  which  this 
change  is  quite  constant,  and  sometimes  most  striking  ;  the  baso- 
philes in  this  disease  may  constitute  5  or  even  10  per  cent,  of  all 
forms  of  leucocytes.  The  increase  may  involve  either  the  finely 
granular,  or  the  coarsely  granular  (mast  cell)  forms,  or  both, 
usually  the  latter. 

Up  to  the  present  time  but  little  attention  has  been  paid  by 
hematologists  to  the  general  circulatory  form  of  basophilia,  al- 
though the  local  increase  of  the  basophiles  under  various  con- 
ditions has  been  well  investigated.  Canon  ^  has  reported  an  in- 
crease of  the  mast  cells  in  a  case  of  chlorosis^  and  in  various  skin 
diseases.  Sherrington  ^  has  observed  a  similar  blood  change  in 
patients  dying  in  the  reaction  stage  of  Asiatic  cJwlera.  A.  E. 
Taylor  ^  states  that  he  has  seen  a  notable  circulatory  basophiHa 
in  a  case  of  carcinoma,  with  marked  cachexia,  but  without  bone 
metastases  ;  in  a  case  of  gonorrhea ;  in  a  case  of  mycosis  fun- 
goides ;  and  in  two  cases  of  septic  bone  disease.  Basophilia  has 
also  been  observed  in  some  cases  of  splenic  anemia. 

Owing  to  our  imperfect  understanding  of  this  condition,  no 
theory  regarding  the  production  of  basophilia  is  as  yet  generally 
acceptable.  It  is  possibly  due  to  the  influence  of  a  specific 
chemotactic  substance,  in  response  to  which  the  basophiles  are 
attracted  from  the  bone  marrow,  and  enter  the  general  circula- 
tion. 

VII.      MYELEMIA. 

The  presence  in  the  circulating  blood  of  myelocytes,  in  small 
or  in  large  numbers,  is  known  as  myelcmia.  As  pre\iously  re- 
marked, this  condition  is  invariably  to  be  regarded  as  patholog- 
ical, since  myelocytes  are  never  found  in  the  blood  of  the  normal 
individual. 

The  most  striking  example  of  myelemia  is  to  be  found 
in  the  spleno-medullary  form  of  leukoma,  in  which  condition  this 
change  constitutes  one  of  the  most  conspicuous  features  of  the 
blood-picture.  Myelocytes  occur  in  the  blood  in  this  disease  in 
greater  absolute  and  relative  numbers  and  with  greater  constancy 

^  Deut.  med.  Woch.,  1892,  vol.  xviii.,  p.  206. 
2Proc.  of  the  Roy.  Soc.  London,  1894,  vol.  Iv.,  p.  189. 

3  "Contributions  from  the  William  Pepper  Laboratory  of  Clinical  Medicine," 
Phila. ,  1900,  p.  148. 


LEUCOPENIA.  203 

than  in  any  other  condition — a  fact  which  is  of  the  greatest  diag- 
nostic value.  The  degree  of  increase  may  be  enormous,  as  illus- 
trated by  a  case  of  the  author's,  in  which  the  actual  number  of 
myelocytes  was  found  to  be  192,738  per  cubic  millimeter,  or 
27.3  per  cent,  of  all  forms  of  cells  in  a  total  leucocyte  count  of 
706,000. 

Less  frequently  myelocytes  are  observed  in  lymphatic  leu- 
kemia and  in  Hodgkin' s  disease,  but  in  these  conditions  their 
occurrence  is  inconstant  and  their  increase  trivial.  Small  num- 
bers of  myelocytes  (from  .5  to  2  or  3  per  cent.)  are  found  in 
almost  every  case  of  primary  pei'nicioiis  anemia,  and  are  not  un- 
common in  marked  cases  of  chlorosis  and  in  many  of  the  severe 
forms  of  secondary  anemia  due  to  various  causes.  They  are  fre- 
quently met  with  in  such  conditions  as  pneumonia,  septicemia, 
diphtheria,  syphilis,  malignant  disease,  rachitis,  tuberculosis,  osteo- 
mvelitis,  osteomalacia,  Addison's  disease,  and  the  malarial  fevers. 
The  writer  has  found  them  also  in  the  following  conditions :  car- 
bon monoxide  poisoning,  hepatic  cirrhosis,  acute  gout,  malignant 
endocarditis,  exophthalmic  goitre,  as  well  as  in  the  above-named 
affections.  One  is  forcibly  impressed  with  the  almost  constant 
presence  of  myelocytes  in  the  estivo-autumnal  type  of  malarial 
fever,  in  severe  septic  infections,  and  in  enteric  fever  in  childhood, 
both  in  the  early  stages  of  the  disease  and  during  the  later,  post- 
febrile anemic  period.  Small  numbers  of  myelocytes  have  been 
reported  also  in  many  other  conditions,  chiefly  those  associated 
with  leucocytosis,  with  anemia,  or  with  both. 

Increased  activity  of  the  bone  marrow,  whereby  the  myelocytes 
are  forced  into  the  blood-stream,  is  in  all  probability  responsible 
for  the  production  of  myelemia.  In  response  to  an  increased 
demand  for  leucocytes,  the  marrow  becomes  so  over-stimulated 
that  many  immature  forms  of  leucocytes,  or  myelocytes,  acciden- 
tally find  their  way  into  the  general  circulation,  their  passage  from 
the  marrow  no  doubt  being  accomplished  largely  by  emigration. 
It  is  furthermore  now  believed  that  substances  which  are  posi- 
tively chemotactic  for  the  polynuclear  neutrophiles  also  exert  a 
similar  attractive  influence  upon  their  immediate  precursors,  the 
myelocytes,  stimulating  their  increased  proliferation  in  the  bone 
marrow  and  exciting  their  emigration  from  this  tissue  into  the 
blood-stream. 

VIII.     LEUCOPENIA. 

Decrease  below  the  normal  standard  in  the  number  of  leuco- 
cytes in  the  peripheral  blood  is  known  as  leucopenia  or  hypoleuco- 
cytosis.     Such  a  condition,  like  its  antithesis,  leucocytosis,  may  be 


204  THE    LEUCOCYTES. 

the  result  of  either  physiolgiocal  or  pathological  causes.  Owing- 
to  the  variation  in  the  normal  number  of  eucocytes  in  different 
individuals,  it  is  difficult  to  determine  arbitrarily  just  what  degree 
of  decrease  may  be  considered  as  a  leucopenia,  but  it  is  safe  to 
apply  the  term  to  any  leuecocyte  count  decidedly  below  5,000 
cells  to  the  cubic  millimeter.  The  number  of  leucocytes  is  rarely 
reduced  to  less  than  3,000,  except  in  certain  of  the  essential 
anemias,  in  which  their  decline  to  one-tenth  the  maximum  normal 
figure  or  even  less,  is  occasionally  to  be  observed.  The  most 
extreme  instance  of  leucopenia  on  record  has  been  reported  by 
Koblanck,^  who  found  but  a  single  leucocyte  in  a  careful  search 
through  twenty  stained  cover-glass  preparations  of  blood  from  a 
man,  of  twent>^-five  years,  suffering  from  epilepsy ;  the  exacty 
numerical  estimate  of  the  leucocytes  in  this  case  is  not  given  in 
detail. 

The  decrease  may  be  accompanied  by  no  deviation  from  the 
normal  percentages  of  the  different  varieties  of  leucoc}i:es,  or  it 
may  involve  a  more  or  less  decided  gain  in  the  lymphocytes,  the 
latter  being  the  more  common  change  of  the  two. 

Accoding  to  the  nature  of  its  underlying  causes,  leucopenia 
may  be  considered  clinically  as  either  physiological  or  as  patho- 
logical. 

Physiological  Leucopenia. 

The  decrease  in  the  number  of  leucocytes  observed  in  several 
physiological  states  is  generally  attributed  to  vasomotor  influ- 
ences which  produce  changes  in  the  distribution  of  the  leucocjiies 
throughout  the  system.  Such  changes  occur  from  the  effect  of 
prolonged  cold,  and  brief  hot,  baths r  Decastelle  '  has  found  that 
a  temporary  leucopenia  may  be  produced  experimentally,  by  stim- 
ulation of  sensory  nerves,  this  procedure  causing  a  reflex  con- 
traction of  the  abdominal  vessels  and  a  consequent  retention  of 
large  numbers  of  circulating  leucocytes  in  this  part  of  the  vascu- 
lar system.  The  variations  in  the  number  of  cells  ranges  from 
twenty  to  thirty  per  cent,  of  the  original  count ;  the  maximum 
decrease  occurs  usually  within  three  or  four  minutes,  and  in  most 
instances  does  not  persist  longer  than  ten  or  fifteen  minutes. 
Reduetiofi  of  blood-pressure  is  promptly  followed  by  a  very  transient 
diminution  in  the  leucocytes  of  the  peripheral  blood. 

Ma/nutrition  and  starvation  are  also  potent  factors  in  the  pro- 
duction of  leucopenia,  the  decrease  dependent  upon  such  causes 
frequently  being  most  pronounced.     The  much-cited  case  of  the 

^  Inaug.  Dissert.,  Berlin,  1889. 

^  Winternitz  :  loc.   cit. 

3^Vien.  klin.  ^Voch.,  1899,  vol.  xii.,  p.  395. 


LEUCOPENIA.  205 

faster,  Sued,  is  a  good  example  of  the  effects  produced  upon  the 
leucocytes  by  abstinence  from  food.  Luciani  ^  found  in  the  blood 
of  this  individual  a  decrease  in  the  number  of  leucocytes  from 
14,530  to  861  per  cubic  millimeter  after  a  seven  days'  fast;  on 
the  eighth  day  an  increase  to  1,530  occurred,  this  being  the 
average  count  noted  during  the  remaining  twenty-two  days  of 
the  fast.  The  subnormal  leucocyte  counts  which  are  often  met 
with  in  many  of  the  infirm  and  the  greatly  enfeebled  can  be 
traced  to  the  effects  of  faulty  nutrition,  and  to  the  malassimila- 
tion  of  food. 

Pathological  Leucopenia. 

Leucopenia,  or  at  least  an  absence  of  leucocytosis,  occurs  dur- 
ing the  course  of  a  number  of  general  infectious  diseases,  promi- 
nent among  which  are  the  following  :  enteric  fever,  measles,  in- 
fluenza, leprosy,  Malta  fever,  the  malarial  fevers,  and  various 
forms  of  non-septic  tuberculosis.  In  certain  of  the  acute  infections 
which  are  ordinarily  accompanied  by  leucocytosis  the  combined 
influences  of  an  intense  infection  and  feeble  resisting  powers  on 
the  part  of  the  individual  may  produce  a  distinct  leucopenia,  or 
may  prevent  the  development  of  the  characteristic  increase.  This 
is  well  illustrated  by  the  low  counts  which  sometimes  are  found 
in  severe  cases  of  pneumonia  and  of  appendicitis. 

Leucopenia,  often  pronounced,  is  not  uncommon  in  chlorosis 
and  in  pernicious  aiiemia,  being  much  more  frequent  and  more 
decided  in  the  latter  disease.  A  well-marked  leucopenia  may  be 
expected  in  about  one-fourth  of  all  cases  of  chlorosis,  and  in 
quite  three-fourths  of  cases  of  pernicious  anemia.  It  is  also  often 
met  with  in  some  high-grade  secondary  anemias,  notably  in  those 
due  to  syphilis  and  to  rachitis,  and  in  splenic  anemia. 

D'Orlandi^  has  called  attention  to  the  frequency  with  which 
leucopenia  is  observed  in  certain  of  the  severer  forms  of  chronic 
gastro-enteritis  in  young  infants. 

In  the  anemias  accompanied  by  a  decrease  in  the  leucocytes, 
especially  in  primary  pernicious  anemia,  the  rule  holds  good  that 
the  more  intense  the  oligocythemia  and  oligochromemia,  the 
greater  the  degree  of  leucopenia.  Ehrlich^  attributes  the  de- 
crease in  such  cases  to  a  lessened  proliferative  function  of  the 
bone  marrow,  in  consequence  of  which  there  is  a  diminution  in 
the  output  of  leucocytes  by  this  organ. 

*  **Das  Hungern"  (German  translation  by  O.  Frankel),  Hamburg  and  Leipzig, 
1890. 

2  Rev.  Mensuelle  des  Malad.  del'Enfance,  1899,  vol.  xvii.,  p.  300. 
^Loc.  cit. 


206  THE    LEUCOCYTES. 

In  leukemia  an  acute  intercurrent  infection  may  produce  an 
abrupt  and  marked  fall  in  the  number  of  leucocytes,  as  in  Cabot's 
remarkable  case  of  lymphatic  leukemia,^  in  which,  as  the  conse- 
quence of  a  fatal  septicemia,  the  leucocytes  fell  in  three  weeks 
from  40,000  to  419  per  cubic  millimeter. 

Decrease  in  the  number  of  leucocytes  may  be  caused  experi- 
mentally, by  the  administration  of  various  drugs  and  other  sub- 
stances. Bohland '  found  that  it  followed  the  injection  of  ergot, 
SHlpho?ial,  tannic  acid,  camphoric  acid,  atropine,  agaracine,  and 
picrotoxine.  Delezene's  ^  investigations  showed  that  a  marked 
decrease  results  from  the  injection  of  various  anticoagulant  sub- 
stances, such  as  peptone,  diastase,  and  eel-serum ;  he  attributes 
the  leucopenia  thus  produced  to  two  factors — actual  destruction 
in  the  circulation  of  some  of  the  leucocytes,  and  dilatation  of  the 
blood-vessels  in  which  the  undestroyed  cells  tend  to  accumu- 
late. The  transient  leucopenia  which  precedes  an  increase  in 
the  leucocytes  has  been  discussed  elsewhere.     (See  page   185.) 

1  Loc.  cit. 
'  2  Loc.  cit. 

^Nouveaux  Montpel.  Med.,  1898,  nrs.  31-34. 


SECTION  V. 


DISEASES    OF   THE    BLOOD. 


very 

.nterfere 

auring  this 


'^'^  a  IS  more 

^-crease  being 

of  hemoglobin. 

elaborate  researches 

.orotic  blood  exhibits  an 

•ity  which  occurs  in  healthy 

y.      In  the  36  cases  studied  by 

.y  ranged  from  1030  to  1049,  these 

jrosis,"  London,  1897,  p.  18. 


SECTION  V. 
DISEASES    OF   THE   BLOOD. 


I.     CHLOROSIS. 

The  blood  drop  is  exceedingly  pale  and  watery- 
Appearance    looking,  and  flows  so  abundantly  from  the  punc- 
OF  THE         ture  that  it  actually  seems  as  if  the  whole  mass 
Fresh  Blood,  of  blood  in  the  body  must  be  increased  ;  a  large- 
sized  drop  usually  follows  the  slightest  prick  of 
the  needle,  in  spite  of  the  obviously  anemic  appearance  of  the 
patient — a  marked  contrast  to  the  difficulty  commonly  experi- 
enced in  pernicious  anemia  of  obtaining  enough  blood  for  the 
examination.     The  blood  spread  out  in  a  film  over  the  finger  is 
transparent  rather  than  opaque,  and  its  fluidity  is  most  striking. 
Microscopical  examination  of  the  fresh  film  shows  excessive 
pallor  of  most  of  the  erythrocytes,  together  with  the  presence  of 
a  variable  number  of  cells  of  smaller  diameter  than  normal,  in 
the  average  case,  and  of  cells  decidedly  deformed  in   shape,  in 
severe   cases.     The    practised   observer    can   determine    at    first 
glance  that  the  number  of  erythrocytes  is  not  greatly  decreased, 
except  in  an  occasional  case  in  which   the  oligocythemia  may  be 
so  marked  as  to  lead  him  to  infer  that  he  is  deahng  with  a  well- 
defined  secondary  anemia. 

Coagulation  of  the  blood  drop,  in  spite  of  the 

Coagulation,  fact  that  hyperinosis  is  absent,  is  generally  very 

rapid  in  chlorosis,  often  so  rapid  as  to  interfere 

with  the  technique  of  the  examination,  if  one  delays  during  this 

procedure. 

The  specific  gravity  of  the  whole  blood  is  more 

Specific       or  less  diminished,  the  degree  of  decrease  being 

Gravity.       closely  parallel   with  the    loss   of  hemoglobin. 

Lloyd  Jones, ^  who  has  made  elaborate  researches 

concerning  this  subject,  believes  that  chlorotic  blood  exhibits  an 

^^^.ggersition  of  the  fall  in  specific  gravity  which  occurs  in  healthy 

girls  at  about  the  age  of  puberty.      In  the  36  cases  studied  by 

this  author  the  specific  gravity  ranged  from  1030  to  1049,  these 

^''Chlorosis,"  London,  1897,  p.  18. 
14 


210  DISEASES    OF    THE    BLOOD. 

figures  corresponding  to  17  and  58  per  cent,  of  hemoglobin,  re- 
spectively, as  estimated  by  the  von  Fleischl  hemometer.  In  30 
cases  Hammerschlag  ^  found  that  the  density  of  the  whole  blood 
averaged  1045,  and  of  the  serum,  1030. 

Most    obser- 
FiG.  37.  Alkalinity,     vers      maintain 

that  in  this  dis- 
'^^  ^m^  ease  the  alkalinity  of  the  whole 

C^       £%  ^"^  t^^v         blood  generally  remains  normal, 
Ql^  ^^    <^  w        or  suffers  but  a  trifling  diminu- 


^  r\  W^        —  to  the  condition  found  in  other 


.-^         ---^  tion,  this  being  in  direct  contrast 

.0    > 


C^.Tl^^O^ 


forms   of  anemia,   in   which  the 

<^  %si^     "^ "  fall    in    the    alkalinity   figure    is 

J     ^^                 C?  *.  usually    pronounced.      Burmin," 

^3  T\      itek         >^  O  in    18   examinations  of  9  cases, 

C^^^r*  £^  found    that    it    ranged  between 

%^  0.128    and  0.200   grm.   NaOH, 

Changes  in  the  erythrocytes  in  the  normal   figures  of  this  inves- 

CHLOROSis.     (Triacid  stain.)  ,.        ,         !•         ^,o^i.      ^^,0-_   

.         .  tiffator  bemg  0.182  to  0.218  grm. 

Showing  a  general  decrease  in  the  diameter         *-*  _      .  ,  ,       .     . 

of  the  corpuscles,  striking  decolorization,  and  111   O   Ol     thCSC   CaSCS  tlie   aclmmiS- 

moderate   poikilocytosis.      The   nucleated    cell  .       ,•  r    •  r   11  J     u 

near  the  center  of  the  field  is  a  normoblast.  tratlOn     of    irOnwaS  tOllOWed     by 

a  marked  increase  in  the  alkalinity 
of  the  blood,  closely  paralleling  the  gain  in  hemoglobin  and  ery- 
throcytes.    On  the  other  hand,  Graeber^  states  that  in  many  cases 
he  discovered  abnormally  high  alkalinity  figures,  so  constantly, 
indeed,  that  he  regarded  them  as  **  specific  for  this  condition." 
The  decrease  in  the  percentage  of  hemoglobin 
Hemoglobin    is  usually  excessive  in  comparison  with  the  re- 
AND  duction  in  the  number  of  erythrocytes,  this  dis- 

Erythrocytes.  proportionate  oligochromemia  being  the  most 
conspicuous  and  most  constant  feature  of  the 
changes  affecting  chlorotic  blood.  Naturally,  such  a  change 
gives  rise  to  very  low  color  indices.  This  statement  applies  only 
to  the  majority  of  cases,  for  a  low  color  index,  while  it  is  the  rule 
in  chlorosis,  and  is,  diagnostically,  a  most  important  feature  of 
the  blood-picture,  is  by  no  means  invariably  found — no  more  in- 
variably than  a  high  color  index  in  pernicious  anemia.  To  illus- 
trate this  point,  it  will  be  observed  that  of  the  io6  cases  of  chlo- 
rosis blood  counts  collected  in  Table  I.,  49  (or  more  than  46  per 
cent.)  showed  an  index  below  0.50,  the  average  for  the  series 

iWien.  Med.  Presse,  1894,  vol.  xliv. ,  p.  1068. 
2Zeitschr.  f.  klin.  Med.,  1900,  vol.  xxxix. ,  p.  365. 
3"Zurklin.  Diag.  d.  Blutkrankheit,"  Leipzig,  1S90,  p.  289. 


CHLOROSIS.  211 

being  0.51,  the  maximum  i.oi,  and  the  minimum  0.22.  In  this 
table  are  given  the  ''first  counts,"  or  those  made  when  the 
patient  first  applied  for  treatment. 

The  average  loss  of  hemoglobin,  as  evidenced  by  this  same 
series  of  cases,  amounts  to  a  trifle  less  than  60  per  cent.,  in  con- 
trast to  which  stands  the  mean  average  erythrocyte  decrease, 
which  is  equivalent  to  about  20  per  cent.,  the  hemoglobin  loss 
thus  averaging  about  three  times  as  great  as  that  of  the  corpus- 
cles. Individually,  the  hemoglobin  percentage  ranged  in  these 
cases  from  12  to  75,  averaging  41.3,  and  the  count  of  erythro- 
cytes from  1,720,000  to  5,600,000,  averaging  3,876,712.  On 
account  of  their  rather  close  correspondence,  it  is  interesting  to 
compare  with  these  figures  the  results  obtained  by  Cabot  ^  in 
109  cases  and  those  of  Thayer  ^  for  63  cases.  Cabot's  cases 
gave  the  following  mean  averages  :  hemoglobin,  41.2  per  cent.; 
erythrocytes,  4,112,000,  with  individual  counts  ranging  frorn 
1,932,000  to  7,100,000.  In  Thayer's  series  the  hemoglobin 
averaged  42.3  per  cent,  and  the  erythrocyte  count  4,096,544. 
Somewhat  lower  figures  are  given  by  Bramwell,^  who  found  the 
following  averages  in  a  series  of  80  cases  :  hemoglobin,  34  per 
cent.,  or  from  10  to  60  per  cent.;  erythrocytes,  3,437,300,  or 
from  1,425,000  to  5,200,000  per  cubic  millimeter;  and  color 
index,  0.49,  or  from  0.20  to  0.96. 

While  numerous  examples  may  be  found  in  Table  I.  of  typ- 
ical cases  of  chlorosis  in  which  the  hemoglobin  estimate  and  ery- 
throcyte count  resemble  those  commonly  occurring  in  pernicious 
anemia  or  in  the  secondary  anemias,  nothing  is  more  characteris- 
tic of  chlorosis  than  the  averages  above  mentioned.  The  great 
difference  is  between  chlorosis  and  pernicious  anemia,  the  index 
usually  being  high  and  the  corpuscular  loss  extreme  in  the  latter 
disease.  As  compared  with  the  secondary  anemias,  the  differ- 
ence is  too  slight  and  its  occurrence  too  inconstant  to  enable  one 
to  regard  it  with  any  degree  of  certainty  from  a  clinical  standpoint. 
Theoretically,  in  secondary  anemia  the  hemoglobin  loss  is  fairly 
proportionate  to  the  erythrocyte  decrease,  thus  producing  color 
indices  at  or  somewhat  below  the  normal,  but  cases  of  secondary 
anemia  having  a  so-called  ''  chlorotic  "  type  of  blood  are  far  too 
common  to  render  any  information  reliable  gained  by  a  sim- 
ple inquiry  into  the  changes  affecting  the  erythrocytes  and  their 
hemoglobin  content. 

^  Loc.  cit. 

2Cited  by  Osier:   "American  Text-book  of  Theory  and  Practice  of  Medicine," 
Phila.,  1894,  vol.   ii.,  p.  196. 

3**  Anemia,"  etc.,  London,  1899,  p.  35. 


Table  I. 
Hemoglobin,  Erythrocytes,  and  Leucocytes   in  Chlorosis,  at  the  First 

Examination.     io6  Cases. 


u 

it 

B 

3 

2 

.5  «• 

^  bo 

0  ca 

X 

s 

u 

is 

•5-S 

u 

E 
2 

Eli 

X 

u 

•o 

c 

u 
0 

■ythrocytes 
r  cb.  mm. 

eucocytes 
r  cb.  mm. 

53  f^ 

U 

^S. 

i 

aft. 

s 

1       i^  A 

I 

55 

.49 

5,600,000 

6,000 

,  54 

25 

•32 

3,910,000 

1 

6,000 

2 

65 

•59 

1  5,500,000 

12,000 

i  55 

30 

•38 

3,890,500 

6,000 

3 

65 

•59 

'  5,500,000 

9,000 

56 

30 

■39 

3,882,000 

7,000 

4 

45 

.41 

1  5,420,000 

11,800 

'  57 

65 

•84 

3,880,000 

4,000 

5 

35 

'33 

5,300,000 

3,000 

^  58 

50 

.66 

3,800,000 

15,000 

6 

35 

'33 

5,200,000 

21,000 

59 

40 

•53 

3,800,000 

9,370 

7 

71 

.68 

5,180,000 

7,500 

60 

38 

•50 

3,780,000 

9,500 

8 

65 

•63 

5,140,000 

4,500 

61 

62 

■83 

3,750,000 

8,000 

9 

65 

.63 

5,100,000 

6,000 

62 

40 

•53 

3,750,000 

6,400 

10 

45 

.44 

5,080,000 

6,000 

63 

35 

.46 

3,750,000 

8,333 

II 

70 

.70 

5,000,000 

5,000 

64 

30 

,40 

3,735,000 

12,400 

12 

55 

.55 

5,000,000 

4,200 

1  65 

75 

1. 01 

3,700,000 

8,000 

13 

52 

.52 

5,000,000 

7,000 

66 

43 

•58 

3,700,000 

5,000 

14 

65 

.66 

4,870,000 

3,000 

67 

20 

•27 

3,685,000 

4,000 

15 

40 

.41 

4,860,000 

8,500 

68 

40 

•55 

3,624,000 

9,000 

i6 

65 

•67 

4,800,000 

6,000 

69 

31 

■43 

3,611,000 

3,400 

17 

60 

.62 

4,800,000 

5,600 

70 

58 

.81 

3,600,000 

8,000 

i8 

50 

.52 

4,800,000 

10,000 

71 

44 

.61 

3,600,000 

7,680 

19 

60 

.64 

4,660,000 

2,000 

72 

40 

.56 

3,550,000 

2,000 

20 

55 

•59 

4,640,000 

7,000 

i  73 

34 

.48 

3,550,000 

4,600 

21 

45 

•48 

4,625,000 

5,000 

1  74 

28 

•39 

3,540,000 

7,800 

22 

60 

•65 

4,600,000 

12,000 

I  75 

33 

•47 

3,520,000 

8  000 

23 

45 

.48 

4,600,000 

6,000 

1  76 

42 

.60 

3,500,000 

9,000 

24 

55 

.60 

4,560,000 

9,000 

77 

38 

•54 

3,500,000 

4,800 

25 

60 

.66 

4,520,000 

17,000 

78 

30 

•43 

3,500,000 

17,000 

26 

40 

.44 

4,520,000 

14,000 

79 

30 

.43 

3,500,000 

7,100 

27 

50 

•55 

4,500,000 

7,000 

80 

35 

•55 

3,200,000 

8,000 

28 

40 

.44 

4,500,000 

4,000 

81 

23 

•36 

3,200,000 

5,000 

29 

20 

.22 

4,500,000 

11,000 

82 

20 

•31 

3,200,000 

9,000 

30 

43 

•48 

4,400,000 

7,000 

83  1 

25   ! 

.40 

3,100,000 

4,000 

31 

40 

•45 

4,400,000 

9, coo 

84 ! 

20  j 

.32 

3, 100,000 

5,000 

32 

30 

'33 

4,400,000 

5,000 

85  : 

38  ' 

•63 

3,000,000 

4,500 

33 

60 

.68. 

4,391,000 

4,200 

i  86  i 

30 

•50 

3,000,000 

4,000 

34 

65 

•74 

4,380,000 

7,400  ! 

'  87 

27 

•45 

3,000,000 

6,000 

35 

43 

•49 

4,320,000 

8, 000  i 

88 

20 

•34 

2,912,000 

2,500 

36 

33 

.38 

4,320,000 

11,200 

89 

28  1 

.48 

2,900,000 

4,oco 

37 

45 

•52 

4,300,000 

6,000  i 

90 

21 

•37 

2,844,000 

7,480 

38 

52 

.61 

4,240,000 

8,000  : 

91 

20  ; 

•36 

2,800,000 

10,000 

39 

34 

.40 

4,230,000 

2,400 

92 

27  ! 

.48 

2,780,000 

8,000 

*o 

65 

•77 

4.210,000 

9,200 

93 

33 

.60 

2,770,000 

9,000 

+1 

58 

.69 

4,204,000 

3,500 

94 

20 

.36 

2,740,000 

2,700 

42 

55 

.65 

4,200,000 

5,000 

95 

22 

•41 

2,660,000 

12,000 

+3 

50 

•59 

4,200,000  j 

4,000 

96  i 

26 

•49 

2,630,000 ! 

2,400 

W 

38 

•45 

4,200,000  , 

S,ooo 

97  1 

23 

•44 

2,600,000 

8,400 

^5 

50 

•59 

4,190,000  , 

6,800  i 

98 

22 

•42 

2,600,000  1 

12,000 

^6 

50 

.60 

4,150,000 

5,000 

99 

46 

•95 

2,420,000  I 

8,000 

47 

60 

•73 

4, 100,000 

5,000 

100 

22 

.46 

2,400,000  j 

6,100 

48 

45 

•55 

4,070,000 

6,500 

lOI 

17 

•36 

2,350,000 

4,000 

49 

55 

.69 

4,000,000 

4,000 

102 

30 

.70 

2,138,000 

6,100 

50 

50 

.62 

4,000,000  ' 

3,050 

103 

30 

•71 

2,100,000 

6,000 

51 

45 

•56 

4,000,000 

15,000 

104 

30 

•72 

2,080,000 

4,000 

52 

40 

.50 

4,000,000 

9,500 

105 

18 

•50 

1,800,000 

2,100 

53 

27 

•34 

4,000,000 

8,000 

106 

12 

•35 

1,720,000 

3,000 

1 

Aver. 

41-3 

0.51 

3,876,712  i 

7,090 

CHLOROSIS.  213 

The  most  conspicuous  change  to  be  observed  in  the  stained 
film  of  chlorotic  blood  is  the  presence  of  large  numbers  of  under- 
sized, pale  erythrocytes,  such  cells  usually  being  so  numerous 
that  one  is  forcibly  impressed  with  the  fact  that  there  must  be  a 
general  decrease  in  the  average  diameter  of  all  the  erythrocytes 
in  the  field.  As  a  rule,  this  decrease  in  size  involves  a  large 
number  of  corpuscles  moderately,  rather  than  a  few  to  an  ex- 
treme degree,  and  therefore,  except  in  severe  cases  associated 
with  marked  oligocythemia,  striking  examples  of  microcytosis  are 
wanting.  This  alteration  is  just  the  opposite  of  what  is  generally 
found  in  pernicious  anemia,  for  in  this  disease  a  tendency  to- 
ward an  increase  in  the  average  diameter  of  the  erythrocytes, 
frequently  in  association  with  the  presence  of  many  extremely 
small  microcytes,  is  the  rule.  If  well  defined,  this  feature  of  the 
blood  changes  carries  a  certain  amount  of  diagnostic  significance, 
although  it  cannot  be  distinguished  in  every  case  of  chlorosis, 
since  in  some  the  diameter  of  the  erythrocytes  appears  to  be 
unaltered,  while  in  others  the  deformities  of  size  may  so  affect  the 
cells  that  the  blood-picture  resembles  that  of  a  severe  secondary 
anemia. 

The  pallor  of  the  erythrocytes,  shown  by  their  feeble  reaction 
toward  the  plasma  stain,  is  at  once  apparent.  The  great  majority 
of  the  cells  are  affected  alike,  being  pale,  often  quite  colorless  in 
the  center  and  gradually  becoming  of  darker  color  toward  the 
peripheiy,  in  which  a  certain  amount  of  hemoglobin  still  remains. 
This  portion  of  the  cell  is  usually  well  stained,  so  that  the  cor- 
puscles frequently  appear  as  hoops  or  rings  ;  some,  however,  do 
not  show  even  this  narrow  hemoglobin-filled  zone,  being  practi- 
cally decolorized  throughout.  Stroma  degeneration,  as  shown  by 
the  changes  described  by  Maragliano,  is  not  demonstrable  in  the 
average  case  of  moderate  severity,  but  this  process  has  been  ob- 
served in  occasional  cases  of  high  grade.  Polychromatophilia, 
except  in  cases  of  the  latter  class,  does  not  occur. 

Basophilic  gramdatioiis  in  the  erythrocytes  are  not  found  in 
this  condition,  according  to  Grawitz.^ 

Deformities  of  shape  are  not  noticeable,  as  a  rule,  except  in 
the  severer  types  of  the  disorder.  In  such  cases,  in  which  both 
the  hemoglobin  and  the  cellular  losses  are  excessive,  poikilo- 
cytosis  may  be  very  striking,  as  great,  in  fact,  as  in  any  blood 
disease,  not  excepting  pernicious  anemia.  Poikilocytes,  should 
they  occur,  are  almost  invariably  of  small  size. 

Nucleated  erythrocytes  are  very  rare.  In  the  average  case 
they  are  usually  sought  for  in  vain,  and  even  in  the  severer  forms 

^  Loc.  cit. 


214 


DISEASES    OF    THE    BLOOD. 


of  chlorosis  these  cells  are  not  numerous.      Erythroblasts  con- 
forming to  the  normoblastic  t}'pe  are   found  almost  exclusively  ; 
megaloblasts,  although  they  are   seen    now   and   then,  are  ex- 
tremely uncommon,  and  have  never  been  found  in  a  large  relative 
or  absolute  proportion  to  the  other  form  of  nucleated  er>^throcytes. 
The  number  of  leucocytes  per  cubic  millimeter 
Leucocytes,    is,  as  a  rule,  normal  in  the  typical  case  of  chloro- 
sis.     If  leucocytosis  occurs,  as  it  does  occasion- 
ally, it  should  be  attributed  to  some  hidden  or  frank  complication  ; 


Table  II. 

Qualitative  Changes  in  the  Leucocytes  in  Chlorosis,  at  the  First 

Examination.     37  Cases. 


Case  No. 

Small  Lymph- 

Large Lymph-    | 

Polynuclear 

Eosinophiles. 

Myelocytes. 

ocytes. 

ocytes. 

Neutrophiles. 

I 

i6;o 

6.0 

76.0 

2.0 

0 

2 

II. 0 

30 

85.5 

0.5 

0 

3 

20.0 

3.5 

75-0 

1.5 

0 

4 

25.0 

3-0 

72.0 

0.0 

0 

5 

19.5 

20.5 

60.0 

0.0 

0 

6 

22.5 

15-0 

62.5 

0.0 

0 

7 

20.5 

19.0 

60.5 

0.0 

0 

8 

32.2 

17.8 

50.0 

0.0 

0 

9 

25-5 

16.0 

57.5 

I.O 

0 

10 

18.5 

12.0 

695 

0.0 

0 

II 

18.0 

lO.O 

72.0 

0.0 

0 

12 

17.0 

21.5 

61.5 

0.0 

0 

13 

19-5 

17.0 

63.0 

0.5 

0 

14 

22.0 

14.5 

63-5 

0.0 

0 

15 

7.5 

12.4 

80.1 

0.0 

0 

16 

193 

21. 1 

59-6 

0.0 

0 

17 

18.5 

16.0 

65.5 

0.0 

0 

18 

18.0 

16.0 

65.0 

1.0 

0 

19 

18.3 

19.0 

61.0 

1-7 

0 

20 

15-5 

245 

60.0 

0.0 

0 

21 

26.0 

21.0 

53-0 

0.0 

0 

22 

12.0 

30.0 

58.0 

0.0 

0 

23 

13.5 

12.5 

73-5 

0.5 

0 

24 

14.0 

15-9 

70.1 

0.0 

0 

25 

17.5 

14.0 

68.5 

0.0 

0 

26 

150 

17.0 

68.0 

0.0 

0 

27 

20.5 

II-5 

68.0 

0.0 

0 

28 

20.3 

12.7 

67.0 

0.0 

0 

29 

31.0 

9.0 

60.0 

0.0 

0 

30 

35-9 

6.0 

58.0 

0.1 

0 

31 

24.0 

2.0 

74.0 

0.0 

0 

32 

275 

40.0 

32.0 

05 

0 

33 

26.0 

15.0 

56.0 

1.0 

2 

34 

24.0 

26.0 

50.0 

0.0 

0 

35 

22.0 

6.0 

72.0 

0.0 

0 

36 

24.5 

14-5 

61.0 

0.0 

0 

37 

6.0 

32.0 

590 

0.0 

Average  :         20. 1 

15-5 

!       64.0 

.31 

•13 

CHLOROSIS.  215 

if  leucopenia  exists,  as  it  sometimes  does,  it  may  nearly  always 
be  regarded  as  a  sign  of  the  severity  of  the  disease,  since  it  is 
rarely  met  with  except  in  cases  in  which  the  hemoglobin  and  ery- 
throcyte losses  are  decidedly  marked.  The  mean  average  num- 
ber of  leucocytes  in  the  106  cases  of  chlorosis  to  which  reference 
has  already  been  made  (Table  I.)  is  7,090  per  cubic  millimeter, 
or  approximately  the  same  as  the  average  count  of  these  cells  in 
normal  blood.  Counts  as  low  as  2,000  and  as  high  as  21,000 
were  made  in  this  series;  and  in  14  of  the  cases  (or  13.2  per 
cent.)  the  increase  was  sufficiently  in  excess  of  the  normal  stan- 
dard to  justify  the  application  of  the  term  leucocytosis,  that  is,  it 
was  in  excess  of  10,000.  These  figures  do  not  differ  materially 
from  those  of  Cabot  and  of  Thayer,  alluded  to  above,  Cabot's 
counts  in  104  cases  averaging  7,400,  and  Thayer's  estimates  in 
63  cases  being  but  slightly  greater,  7,485. 

Relative  lymphocytosis,  usually  marked  in  relation  to  the  se- 
verity of  the  case,  is  a  common,  but  not  a  constant,  qualitative 
change.  It  occurs  in  both  mild  and  severe  cases,  but  is  much 
more  common  in  the  latter.  In  the  author's  experience,  this  in- 
crease involves  chiefly  the  larger  forms  of  these  cells,  both  the 
non-granular  mononuclear  cells  with  spherical  nuclei  and  the  so- 
called  ''transitional"  forms  with  indented  nuclei;  striking  in- 
crease in  the  last  named  variety  of  cells  was  a  notable  differential 
change  in  a  large  proportion  of  the  37  cases  listed  in  Table  II. 
In  many  of  the  cases  in  this  series  the  large  and  small  lympho- 
cytes together  made  up  from  45  to  as  high  as  67.5  per  cent,  of 
all  varieties  of  leucocytes,  the  percentage  of  large  forms  being 
repeatedly  estimated  at  20  or  30,  and  even  40,  in  one  instance. 

Deviations  from  normal  in  the  relative  percentage  of  poly?m- 
clear  neutrophiles  are  governed  by  the  behavior  of  the  lympho- 
cytes, low  differential  counts  of  the  former  type  of  cells  accom- 
panying high  percentages  of  the  latter,  and  vice  versa.  Should 
leucocytosis  exist,  it  is  of  the  pure  polynuclear  neutrophile  type. 

The  eosinophiles  are  notably  decreased,  both  absolutely  and 
relatively.  The  author  has  never  found  an  increase  of  these  cells 
in  chlorosis,  although  considerable  pains  were  taken  to  verify  the 
statements  made  by  some  writers  that  this  variety  of  leucocytes 
is  occasionally  observed  to  be  greatly  above  normal  in  this  con- 
dition. Eosinophiles  were  absent  entirely  in  more  than  seven- 
tenths  of  all  the  cases  collected  in  Table  II.,  and  were  never  found 
to  exceed  2  per  cent,  of  all  the  forms  of  leucocytes. 

Exceptionally,  small  percentages  of  myelocytes  may  be  en- 
countered, as  a  rule,  only  in  cases  of  a  severe  character.  These 
cells  are  ordinarily  present  in  not  more  than  6  per  cent,  of  all 


2l6 


DISEASES    OF    THE    BLOOD. 


cases,  and  their  relative  proportion   to  the  other  forms  of  leuco- 
cytes is  always  trifling,  being  rarely  over  i  or  2  per  cent. 

In  the  great  majority  of  cases  it  has  been  gen- 

Blood  Plaques,  erally  observed  that  the  number  of  plaques  is 

considerably  in  excess  of  normal.     It  appears 

that  these  elements  are  especially  numerous  in  blood  which  clots 

rapidly. 

The  changes  in  the  blood  associated  with  most 
Diagnosis,      well-defined  cases  of  chlorosis  may  be  summarized 
as  follows  : 


Color. 

Coagulation. 
Specific  gravity. 
Hemoglobin. 

Erythrocytes. 


Pale  and  watery. 

Usually  rapid. 

Decreased. 

Marked  absolute  decrease,  in  most  instances 
relatively  greater  than  the  loss  of  erythrocytes, 
thus  producing  a  low  color  index. 

Moderately  decreased,  ordinarily  to  about 
4,000,000  per  cubic  millimeter.  Counts  of 
3,000,000  and  less  are  common  in  severe  cases. 
Erythroblasts  very  rare ;  if  present,  cells  of 
the  normoblastic  type  invariably  predominate. 
General  decrease  in  the  average  diameter  of 
the  erythrocytes.  In  severe  cases  microcy- 
tosis  may  be  marked. 

Poikilocytes   not   numerous,  except  in   severe 
cases. 
Polychromatophilia  rare. 

Usually  normal  in  number. 

Relative  lymphocytosis  common. 

Small  percentages  of  myelocytes,  only  in  severe 

cases. 

Eosinophils  notably  decreased. 

Plaques.  Increased  in  number. 

He  who  would  essay  the  diagnosis  of  chlorosis  solely  by  the 
aid  of  the  information  derived  from  the  blood  examination  is  in- 
deed a  rash  clinician.  This  point  cannot  be  emphasized  too 
strongly,  that  there  is  no  blood-picture  peculiar  to  this  condition, 
since  changes  precisely  similar  to  those  seen  in  many  a  case  of 
typical  chlorosis  are  often  observed  in  the  secondary  anemias, 
especially  in  those  dependent  upon  such  factors  as  syphilis,  tuber- 


Leucocytes. 


CHLOROSIS.  2  I  7 

culosis,  malignant  disease,  and  chronic  renal  lesions.  On  the 
other  hand,  rare  cases  of  chlorosis  have  been  reported  in  which 
no  alterations  in  the  blood  were  discoverable.  The  blood  changes 
enumerated  above  (especially  such  features  as  a  low  color  index, 
the  general  decrease  in  the  diameter  of  the  erythrocytes,  the  ab- 
sence or  scantiness  of  erythroblasts,  and  the  normal  number  of 
leucocytes  associated  v/ith  relative  lymphocytosis  and  a  decrease 
of  the  eosinophiles)  are  not  then,  pathognomonic,  but  simply 
highly  suggestive  of  the  disease  under  discussion,  in  view  of 
which  fact  it  becomes  essential  to  seek  for  other  clinical  signs 
and  to  consider  them  carefully  in  connection  with  the  blood  find- 
ings. One  of  the  most  important  points  which  should  be  borne 
in  mind  is  the  fact  that  chlorosis  is  practically  confined  to  females, 
usually  those  in  early  womanhood,  at  or  near  the  period  of 
puberty.  Chlorosis  is  about  as  compatible  with  the  male  sex  as 
is  pregnancy — the  so-called  *'  male  chlorosis  "  is  nothing  more 
than  a  diagnostic  myth.  Osier  ^  remarks  that  in  girls  in  whom 
the  disease  occurs  early  in  their  teens  precocity  and  almost  prema- 
ture appearance  of  the  menses  is  likely  to  exist.  A  large  propor- 
tion of  those  in  whom  the  disease  develops  later  in  life  complain 
of  scantiness  or  total  suppression  of  the  menstrual  flow  and  of 
dysmenorrhea,  these  symptoms  being  especially  common  in  chlo- 
rotics  in  the  early  twenties  or  thereabouts. 

The  question  of  heredity  also  is  of  some  diagnostic  value,  for 
it  has  been  frequently  noted  that  the  disease  exists,  for  instance, 
in  two  or  more  sisters,  the  statement  being  elicited  upon  further 
inquiry  that  their  mother  suffered  from  chlorosis  at  an  earlier 
period.  Thus,  Albutt  ^  speaks  of  meeting  in  his  consulting-room 
the  chlorotic  daughters  of  women  whom  years  before  he  had 
treated  for  the  same  disorder. 

Among  the  other  manifestations  of  the  disease  to  which  atten- 
tion should  be  paid  the  following  are  the  more  important :  a  pecu- 
liar greenish-yellow  color  of  the  complexion  and  blanching  of  the 
mucous  membranes  (except  in  those  rare  instances  of  chlorosis 
florida,  in  which  the  color  is  high) ;  the  occurrence  of  various 
gastro-intestinal  disturbances,  of  edema  of  the  face  and  lower 
limbs,  of  vertiginous  attacks,  and  of  dyspnea  upon  physical  exer- 
tion ;  and  the  presence  of  systolic  basic  heart  murmurs,  and  a 
venous  hum  most  distinctly  audible  over  the  great  vessels  of  the 
neck.  Slight  enlargement  of  the  thyroid  gland,  frequently  asso- 
ciated with  Joffroy's  sign  (absence  of  horizontal  wrinkling  of  the 
skin  of  the  forehead  and  of  upward  curving  of  the  eye-brows,  when 

^  Loc.  cit. 

2  "System  of  Medicine,"  London  and  N.  Y.,  1898,  vol.   vi.,  p.  483. 


2l8  DISEASES    OF    THE    BLOOD. 

the  patient  glances  suddenly  at  the  ceiling  without  elevating  her 
head),  is  a  physical  sign  which  should  always  make  one  suspicious 
of  chlorosis. 

The  distinctions  between  chlorosis  and  pernicious  anemia,  as 
shown  by  the  blood  examination,  will  be  described  under  the 
latter  disease.     (See  page  230.) 

11.     PERNICIOUS   ANEMIA. 

In  marked  cases  of  pernicious  anemia  it  is 
Appearance  sometimes  almost  impossible  to  obtain  from  a 
OF  the  puncture  of  the  finger-tip  a  sufficient  quantity  of 
Fresh  Blood,  blood  for  an  ordinar)^  chnical  examination,  owing 
to  the  bloodlessness  of  the  superficial  vessels. 
This  fact  naturally  prompts  the  query,  Does  an  actual  reduction 
in  blood  volume  or  oligemia  exist  in  such  an  instance,  or  can  the 
dryness  of  the  superficial  tissues  be  attributed  to  vasomotor  dis- 
turbances causing  an  unequal  distribution  of  the  blood  mass,  in 
favor  of  the  internal  viscera  and  deeper  circulation?  In  a  patient 
in  whom  puncture  of  the  finger  fails  to  give  the  requisite  amount 
of  blood,  the  lobe  of  the  ear  will  generally  be  found  to  yield  a 
drop  of  sufficient  size.  But  even  this  ver>^  vascular  part  of  the 
body  may  in  extreme  cases  seem  practically  bloodless.  The 
writer  recalls  a  case  of  fatal  anemia  in  which,  in  order  to  secure 
a  drop  of  blood  large  enough  to  fill  the  lumen  of  an  erythrocy- 
tometer  only  to  the  o.  5  graduation,  it  was  necessary  to  open  a 
small  superficial  vessel  of  the  scalp,  repeated  deep  punctures  of 
the  fingers,  toes,  and  ear-lobes  having  given  negative  results. 

The  drop  as  it  emerges  from  the  puncture  wound  is  exceed- 
ingly pale,  thin,  and  hydremic,  lacking  the  characteristic  opac- 
ity of  healthy  blood,  and  being  of  a  fluidity  and  general  color 
which  hav^e  been  likened  to  those  of  meat-washings.  In  an  oc- 
casional instance  the  color  of  the  blood  may  be  practically  normal, 
or,  rarely,  of  a  brownish-red  or  chocolate  tint ;  but,  as  a  rule,  it 
resembles  a  watery,  pinkish  fluid,  which  appears  to  be  deficient 
both  in  depth  of  color  and  in  density.  It  has  been  frequently 
observed  that,  after  having  stood  for  a  short  length  of  time,  the 
drop  shows  a  tendency  to  separate  into  two  more  or  less  distinct 
parts,  consisting  of  a  dark  stratum  of  corpuscles  and  a  clear, 
watery-looking  layer  of  plasma;  or  it  may  be  irregularly  mottled 
at  different  points,  as  if  the  corpuscles  had  become  concentrated 
in  isolated,  compact  groups  in  various  parts  of  the  plasma,  thus 
producing  the  effect  of  alternating  dark  and  light  areas  distributed 
through  the  drop. 


PERNICIOUS    ANEMIA.  2ig 

Microscopical  examination  of  the  fresh  film  shows  a  great  re- 
duction in  the  number  of  the  erythrocytes,  together  with  the 
presence  of  many  forms  of  these  cells  which  exhibit  every  possible 
variation  in  size  and  in  shape.  The  color  of  the  individual  eryth- 
rocyte varies,  some  being  normally  dark  and  well  colored, 
while  others  appear  as  mere  washed-out  rings  or  ''phantoms." 
In  some  of  the  cells  the  hemoglobin  appears  to  be  quite  evenly 
distributed  throughout  the  stroma,  so  that  their  typical  biconcav- 
ity  is  obliterated.  The  endoglobular  degenerative  changes  and 
those  structural  alterations  denoting  total  necrosis  of  the  eryth- 
rocytes, previously  described,  may  be  demonstrated  with  great 
clearness  in  this  condition.  Rouleaux  formation  is  either  entirely 
absent,  or  incomplete  and  atypical. 

Owing  to  the  extreme  oligocythemia  common  in  pernicious 
anemia,  it  is  advisable  in  making  the  films  to  use  a  somewhat 
larger  drop  of  blood  than  is  chosen  for  making  ordinary  spreads, 
so  that  the  field  will  not  contain  such  a  pronounced  scarcity  of 
cellular  elements. 

The  obvious  fluidity  of  the  blood,  the  deficiency 
Coagulation,  of  the  fibrin  network,  and  the  slowness  with  which 
coagulation  occurs  are  marked  features  of  this 
disease.  In  fact,  in  some  cases  coagulation  may  be  said  not  to 
occur  at  all,  according  to  the  experiments  of  Hayem  ^  and  others 
of  the  French  school,  as  in  the  case  quoted  by  Lenoble,^  in  which 
no  clotting  of  a  sample  of  arterial  blood  was  observed  even  after 
a  lapse  of  seventy -two  hours  after  its  withdrawal  from  the  ves- 
sels. Many  authors  attribute  considerable  diagnostic  value  to 
this  absence  of  clotting,  and  others  go  so  far  as  to  state  that  it 
renders  a  patient  suffering  with  pernicious  anemia  especially  prone 
to  troublesome  hemorrhages,  even  from  a  slight  finger-prick — an 
accident  which  must  be  extremely  rare,  however,  for  it  practically 
never  complicates  an  ordinary  clinical  examination. 

The    density   of   the    whole    blood    is    much 
Specific       below  the  normal  standard,  specific  gravities  as 
Gravity.       low  as   1027  having    been  reported.      It  is   to 
be  recalled  that  in  cases  with  a  high  color  in- 
dex erroneous  results  may  occur  from  attempting  to   estimate 
the  hemoglobin  percentage  by  Hammerschlag's  table  of  equiv- 
alents,  since    the    hemoglobin,   in   reality,   is    somewhat    higher 
than  the  percentages  corresponding  to  the  specific  gravity  figures. 
(See  page  100.) 

•  Loc.  cit. 

2  "Charact.  semeiol.  du  caillot  et  du  serum,"  Paris,  1898. 


220  DISEASES    OF    THE    BLOOD. 

Up  to  the  present  time,  the  reaction  of  the 
Alkalinity,  blood  in  pernicious  anemia  has  not  been  very 
thoroughly  studied,  but  the  work  already  accom- 
plished is  sufficient  to  show  that  the  alkalinity  is  much  diminished, 
as  in  most  severe  anemias.  That  it  may  be  strikingly  below 
normal  is  shown  by  a  case  lately  reported  by  Waldvogel,'  who 
in  one  case  estimated  the  alkalinity  figure  at  .40  grm.,  using 
Salkowski's  method.  This  author  has  determined  that  the  nor- 
mal alkalinity  for  men  ranges  from  .350  to  .400  grm.,  and  for 
women  from  .300  to  .350  grm. 

Both  the  percentage  of  hemoglobin  and  the 
Hemoglobin    number  of  erythrocytes  are  greatly  diminished, 
AND  the  former,  as  a  general   rule,  relatively  less  so 

Erythrocytes,  than  the  latter.  Thus,  inasmuch  as  the  individual 
corpuscles  contain  often  a  normal  or  even  an  ex- 
cessive amount  of  hemoglobin,  it  follows  that  high  color  indices 
are  common — common  but  by  no  means  constant,  as  seems  to  be 
the  current  impression  among  many  students,  for  although  it  is 
true  that  while  the  average  color  index  is  i.oo  or  higher  in  per- 
nicious anemia  cases,  the  same  statement  cannot  always  be  ap- 
plied to  the  individual  case.  The  author's  series  of  31  cases 
(Table  III.)  showed,  at  the  first  examination,  hemoglobin  percent- 
ages varying  from  a  minimum  of  12  to  a  maximum  of  45,  with  a 
mean  average  of  25.1  ;  the  color  index  of  these  cases  ranged 
from  0.40  to  1.87,  the  average  being  1.08;  in  17  of  the  cases 
(or  54.8  per  cent.)  the  figure  was  i.oo  or  higher.  During  re- 
missions, as  the  erythrocytes  increase,  it  is  common  to  find  low 
indices,  this  peculiarity  being  especially  conspicuous  should  the 
improvement  in  the  patient's  condition  be  rapid,  since  in  such 
instances  the  corpuscular  increase  is  relatively  much  more  rapid 
than  the  gain  in  hemoglobin.  In  cases  in  which  improvement 
takes  place  more  slowly,  the  color  index  is  likely  to  remain 
higher,  for  here  the  corpuscles  and  the  hemoglobin  are  more 
prone  to  increase  proportionately  along  parallel  lines. 

The  oligocythemia  is  most  striking,  counts  of  from  i  ,000,000 
to  2,000,000  erythrocytes  per  cubic  millimeter  being  not  uncom- 
mon when  the  patient  first  comes  under  observation,  the  number 
of  cells  frequently  diminishing  to  about  750,000  or  even  500,000 
later  during  the  course  of  the  disease.  In  Quincke's  often-quoted 
case  the  remarkable  count  of  143,000  per  cubic  millimeter  was 
observed  just  before  the  death  of  the  patient,  an  instance  which 
is  almost  paralleled  by  a  case   recorded   by  Hills,-  in  which   the 

^  Deut.  med.  Woch.,  1900,  vol.  xxvi.,  p.  6S5. 

2  Boston  Med.  and  Surg.  Journ.,  1898,  vol.  cxxxix.,  p.  542, 


PERNICIOUS    ANEMIA. 


221 


erythrocyte  count  fell  to  155,760  one  day  before  death.     In  the 

series  just  mentioned  (Table  III.)  the  count  of  erythrocytes  per 

cubic  miUimeter  averaged   1,343,677,  ranging  between   550,000 

and  3,240,000  ;  this  represents  an  average  loss  in   corpuscular 

matter  of  somewhat  less  than  75  per  cent.,  the  greatest  decrease 

amounting  to  almost  90 

per  cent,    of  normal —  ^i^-  3^- 

a  much  more    striking 

oligocythemia    than    is 

found  in  any  other  form 

of  anemia. 

Periods  of  temporary 
increase  in  the  hemo- 
globin and  erythrocytes, 
followed  sooner  or  later 
by  relapses,  are  com- 
monly observed,  the 
gain  during  such  peri- 
ods sometimes  being 
very  pronounced.  Thus, 
in  one  of  the  cases  tab- 
ulated below  a  gain  of 
more  than  2,500,000 
erythrocytes  to  the  cu- 
bic millimeter  was  noted 
during  a  period  of  six 
weeks,  with  a  subsequent 
loss  of  over  1,000,000  cells  in  the  following  eight  days,  the  color  in- 
dex during  this  time  ranging  from  1.25  to  0.74.  These  periods  of 
improvement  in  the  condition  of  the  blood  are  generally  asso- 
ciated with  an  amelioration  of  the  other  clinical  manifestations  of 
the  disease,  the  patient's  general  condition  improving  so  substan- 
tially that  he  begins  to  consider  himself  on  the  high  road  to  re- 
covery, but  in  the  course  of  time  the  old  sympt^^^jms  return,  and 
the  characteristic  blood-picture  again  becomes  evident.  In  most 
cases  death  is  preceded  by  extreme  oligochromemia  and  oligo- 
cythemia, the  hemoglobin  often  falling  to  1 5  or  20  per  cent,  of 
normal  and  the  erythrocyte  count  declining  to  750,000  or  less  ; 
in  some  cases,  however,  these  losses  are  not  so  marked,  and  the 
count  does  not  fall  below  1,500,000  during  the  whole  course  of 
the  disease. 

A  prominent  characteristic  of  the  blood  in  pernicious  anemia 
is  the  wide  dissimilarity  in  the  size  of  the  erythrocytes,  due  to  the 
presence  of  large  numbers  of  megalocytes  and  microcytes ;  so 


Changes  in  the  erythrocytes  in  pernicious 
ANEMIA.     (Triacid  Stain.) 

Showing  a  general  increase  in  the  diameter  of  the  cor- 
puscles, and  marked  poikilocytosis.  The  nucleated  cell  in 
the  right  of  the  field  is  a  megaloblast. 


DISEASES    OF   THE    BLOOD. 


Table  III. 


Hemoglobin  and  Erythrocytes  in  Pernicious  Anemia,  at  the  First 
Examination.     31  Cases. 


Number. 

Hemoglobin  Per  Cent. 

Color  Index. 

Erythrocytes  per  cb.  mm. 

I 

32 

.40 

3,240,000 

2 

35 

.58 

3,008,500 

3 

40 

.81 

2,468,000 

4 

24 

.52 

2,300,000 

5 

24 

.54 

2,200,000 

6 

24 

.60 

2,000,000 

7 

26 

•71 

1,810,000 

8 

20 

•55 

1,800,000 

9 

40 

1.23 

1,620,000 

10 

23 

■13 

1,562,000 

II 

45 

1-55 

1,448,000 

12 

35 

138 

1,260,000 

13 

30 

1.20 

1,250,000 

14 

20 

.80 

1,237,500 

15 

18 

•73 

1,230,000 

16 

35 

1.48 

1,180,000 

17 

26 

1. 17 

1,100,000 

18 

14 

.67 

1,040,000 

19 

20 

1. 00 

1,000,000 

20 

31 

1.58 

980,000 

21 

18 

1.02 

875,000 

22 

20 

1. 19 

840,000 

23 

30 

1.87 

800,000 

24 

22 

1^38 

795,000 

25 

25 

1.60 

780,000 

26 

15 

.97 

768,000 

27 

20 

1.42 

700,000 

28 

12 

.96 

622,000 

29 

15 

1.20 

620,000 

30 

20 

1-75 

570,000 

31 

20 

1. 81 

550,000 

Average  : 

25  + 

1.08 

1,343,677- 

striking  may  be  this  feature  of  the  blood-picture  that  it  is  some- 
times difficult  to  find  any  two  cells  in  the  same  field  of  the  micro- 
scope which  are.  of  the  same  diameter.  In  the  great  majority  of 
cases  it  will  b  *  round  that  the  megalocytes  distinctly  outnumber 
the  microcytes,  to  such  an  extent  and  in  such  a  large  proportion 
of  cases  that  some  writers  consider  this  change  an  almost  con- 
.stant  blood  finding  in  this  disease.  Large  erythrocytes,  measur- 
ing slightly  below  or  above  10  (jl  in  diameter,  are  veiy  common, 
while  those  measuring  in  the  neighborhood  of  1 5  a  or  even  20  fi 
are  met  with  more  rarely.  Undersized  erythrocytes,  about  3  or 
4  n  in  diameter,  are  also  numerous,  but,  as  remarked  above, 
much  less  so  than  those  of  larger  size.  The  presence  of  small, 
dark-colored,  spherical    microcytes    of  this    size  (the    so-called 


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Red,  Hemoglobin. 


PERNICIOUS    ANEMIA. 

Black,  Erythrocytes. 


Blue,  Leucocytes. 


PERNICIOUS    ANEMIA.  223 

''Eichhorst's  corpuscles  "),  once  regarded  as  pathognomonic  of 
pernicious  anemia,  is  neither  constant  nor  diagnostic  of  this  dis- 
ease, since  they  are  found  in  many  other  anemic  conditions,  and 
are  absent  in  a  large  proportion  of  cases  of  true  pernicious  anemia. 
The  fact  that,  of  these  alterations  in  the  size  of  the  erythrocytes, 
megalocytosis  predominates,  constitutes  a  sign  of  valuable  diag- 
nostic significance  in  this  disease. 

Poikilocytosis,  to  a  more  or  less  marked  degree,  is  constantly 
obsei-ved,  the  conspicuousness  of  the  deformities  being  in  some 
cases  extreme,  while  in  others  the  change  is  a  less  notable  feature. 
While  marked  poikilocytosis  usually  goes  hand  in  hand  with 
excessive  diminution  in  the  number  of  erythrocytes  and  in  the 
amount  of  hemoglobin,  the  association  of  these  three  changes 
cannot  be  invariably  counted  upon,  for  in  some  cases,  in  spite  of 
the  fact  that  both  oligocythemia  and  oligochromemia  are  marked, 
deformities  in  the  shape  of  the  corpuscles  are  but  trifling.  All 
varieties  of  erythrocytes,  small,  large,  nucleated,  and  non-nu- 
cleated, may  be  deformed,  so  that  the  size  of  the  poikilocytes 
varies  from  that  of  the  smallest  microcyte  to  that  of  the  largest 
megalocyte.  The  kinds  of  deformity  are  of  infinite  variety,  but 
it  is  still  possible  to  designate  certain  well-defined  forms  which 
are  especially  common  in  this  disease,  these  being  the  horseshoe 
form  (Litten),  and  the  oval  form  (Cabot),  both  of  which  varieties, 
while  by  no  means  peculiar  to  this  condition,  are  found  so  fre- 
quently and  in  such  abundance  in  pernicious  anemia  that  their 
presence  in  the  blood  is  at  least  highly  suggestive.  Of  these 
two  forms,  the  elongated,  oval  erythrocyte  is  found  more  con- 
stantly, and  has  been  described  in  but  a  few  other  conditions. 
The  author  has  been  struck  with  the  predominance  of  cells  of 
this  sort  in  three  consecutive  cases  of  purpura  hemorrhagica, 
in  one  of  which  the  deformity  was  so  marked  that  scarcely  a 
single  normally  shaped  erythrocyte  could  be  found  in  certain 
fields  of  the  microscope.  Cabot  ^  cites  Greene  as  noticing  the 
same  change  in  the  blood  of  two  patients  in  whom  the  tentative 
diagnosis  of  epidemic  dropsy  had  been  made.  In  addition  to 
these  well-defined  varieties,  many  cells  of  other  shapes,  also  met 
with  in  other  severe  anemias,  are  observed,  notably  those  resemb- 
ling the  form  of  a  sausage,  or  a  spindle,  or  a  club.  (See  Fig. 
38,  page  221.) 

In  the  stained  specimen  the  principal  point  of  interest  is  the 
presence  of  7iucleated  erythrocytes,  upon  the  character  of  which 
the  diagnosis  of  pernicious  anemia  must  depend.  Erythroblasts 
are  always  to  be  found  in  this  disease,  at  some  stage  of  its  course. 

^  Loc.   cit. 


2  24 


DISEASES    OF    THE    BLOOD. 


Megaloblasts  are  of  much  greater  clinical  significance  than  nor- 
moblasts, and  by  a  differential  count  will  be  found  always  to  out- 
number the  latter  in  eveiy  genuine  case  of  pernicious  anemia,  at 
some  stage  of  the  disease.  This  blood-picture,  which  indicates 
a  megaloblastic  degeneration  of  the  bone  marrow,  due  in  all  proba- 
bility to  the  influence  of  some  unknown  but  specific  toxic  agency, 
is  associated  with  only  two  other  conditions,  namely,  nitrobenzole 
poisoning,  and  some  cases  of  high-grade  anemia  due  to  bothri- 
ocephalus  latus  infection.  The  predominance  of  megaloblasts 
over  normoblasts  in  pernicious  anemia  is  well  illustrated  by  Table 
IV.,  which  shows  that  at  the  first  examination  the  former  type  of 


Table  IV. 

Approximate  Number  of  Nucleated  Erythrocytes  per  cb.  mm.  in 
Pernicious  Anemia,  at  the  First  Examination. 


Number. 

Total. 

Megaloblasts. 

Normoblasts. 

Microblasts. 

I 

924 

693 

210 

21 

2 

840 

616 

140 

84 

3 

544 

512 

16 

16 

4 

470 

320 

150 

0 

5 

368 

207 

46 

"5 

6 

336 

240 

90 

6 

7 

'    328 

0 

328 

0 

8 

260 

20 

240 

0 

9 

256 

144 

80 

32 

lO 

250 

180 

70 

0 

II 

235 

175 

60 

0 

12 

224 

168 

56 

0 

13 

204 

148 

56 

0 

H 

200 

160 

40 

0 

IS 

192 

180 

12 

0 

i6 

160 

96 

64 

0 

17 

lOI 

80 

21 

0 

i8 

100 

0 

100 

0 

19 

96 

73 

23 

0 

20 

67 

47 

13 

7 

21 

60 

40 

20 

0 

22 

48 

32 

16 

0 

23 

48 

37 

7 

4 

24 

32 

24 

8 

0 

25 

20 

20 

0 

0 

26 

15 

15 

0 

0 

27 

10 

8 

0 

2 

28 

6 

6 

0 

0 

29 

3 

3 

0 

0 

Average  : 

2204- 

146+ 

64+ 

10 

cells  outnumbered  the  latter  in  26  out  of  the  29  cases  here 
grouped  together.  The  average  proportion  of  megaloblasts  to 
normoblasts  in  this  series  is  somewhat  more  than  2  to  i,  and  in 


PERNICIOUS    ANEMIA.  22 5 

some  cases  the  former  were  the  only  kind  of  erythroblast  dis- 
covered. The  total  number  of  erythroblasts  of  all  varieties  aver- 
aged 220  per  cubic  millimeter  of  blood,  ranging  from  as  low  as 
3  to  as  high  as  924.  Regarding  this  last  statement,  it  should  be 
remembered  that  it  is  not  the  actual  number  of  nucleated  erythro- 
cytes, but  their  character,  which  is  all  important  in  the  diagnosis 
of  this  disease. 

Microblasts  are  rare  in  comparison  to  the  other  forms  of  nu- 
cleated erythrocytes ;  in  some  cases  they  may  be  relatively  nu- 
merous, but  in  the  majority  they  are  absent.  They  were  noted 
in  but  9  of  the  29  cases  tabulated  above  (Table  IV.),  their  average 
number  for  the  series  being  10  to  the  cubic  millimeter.  In  the 
differential  count  of  nucleated  erythrocytes,  microblasts  should 
be  totalled  with  normoblasts,  of  which  they  are  simply  degenerate 
forms,  more  or  less  stripped  of  their  protoplasm,  and  hence  irreg- 
ular and  ragged  in  outline. 

In  addition  to  the  foregoing  types  of  erythroblasts,  cells  pos- 
sessing the  characteristics  of  both  the  normoblast  and  the  meg- 
aloblast  may  be  observed  in  many  instances.  These  atypical 
forms,  and  their  clinical  significance,  have  been  described  in  a 
previous  section.  (See  page  144.)  In  certain  corpuscles,  both 
of  the  normoblastic  and  megaloblastic  types,  division  of  the  nu- 
cleus into  several  parts  may  have  occurred,  and  in  rare  instances 
evidences  of  true  karyokinesis  may  be  seen.  Normoblasts  show- 
ing complete  or  partial  nuclear  extrusion  and  separation  of  the 
nucleus  into  a  clover-leaf  design  are  not  uncommon,  although 
pictures  of  this  sort  are  found  much  more  frequently  in  leukemia. 
In  many  cases  of  pernicious  anemia  one  cannot  but  be  struck 
with  the  fact  that  the  majority  of  these  atypical  forms  appear  as 
cells  with  a  megaloblastic  protoplasm  and  a  normoblastic  nucleus  ; 
they  are,  in  the  author's  experience,  much  more  numerous  in  this 
disease  than  cells  having  a  normoblastic  protoplasm  and  a  meg- 
aloblastic nucleus,  the  latter  being  more  common  in  leukemia. 

Fluctuations  in  the  total  number  of  erythroblasts  occur  from 
time  to  time  during  the  progress  of  the  disease,  these  changes 
sometimes  taking  place  with  great  abruptness,  being  of  wide 
range  and  often  carrying  not  the  slightest  cHnical  import.  A 
marked  increase  usually  but  not  invariably  precedes  and  accom- 
panies a  gain  in  the  number  of  erythrocytes  and  in  the  percentage 
of  hemoglobin  ;  and  a  similar  increase,  usually  associated  with 
extreme  diminution  in  the  erythrocyte  count,  is  commonly  met 
with  as  a  pre-agonal  sign. 

Marked   evidences  of  polyclwomatophilia  are  found  in  many  of 
the  erythrocytes,  both  of  the  nucleated  and  the  non-nucleated 
15 


226 


DISEASES    OF    THE    BLOOD. 


varieties.  Such  cells,  when  stained  with  Ehrlich's  triacid  mix- 
ture, instead  of  taking  the  normal  orange  color  of  the  solution, 
stain  some  bastard  tint,  such  as  slate  color,  or  dull  purple,  or 
dirty  gray.  Others  may  show  a  peculiar,  streaked  appearance, 
and  irregular  pale-white  unstained  areas,  while  others  are  scarcely 

Table  V. 

Number  of  Leucocytes  per  cb.  mm.  and  Percentage  of  Various  Forms  in 
Pernicious  Anemia,  at  the  First  Examination.     31  Cases. 


Percentages  of  Diflfere 

nt  Forms. 

Leucocytes  per 

No. 

cb.  mm. 

Small  lym- 
phocytes. 

Large  lym- 
phocytes. 

Polynuclear 
neutrophil  es. 

Eosinophiles. 

Myelocytes. 

I 

13,000 

43-2 

2.8 

49.6 

2.8 

1.6 

2 

8,200 

7-7 

2.0 

86.2 

1.6 

2.5 

3 

7,000 

14.4 

1.6 

81.6 

2.0 

0.4 

4 

7,000 

13.6 

5-2 

77.6 

2.8 

0.8 

5 

6,400 

34- 0 

4.0 

60.0 

I.O 

I.O 

6 

6,000 

II. 0 

2.0 

84.0 

I.O 

2.0 

7 

5,800 

14.0 

3.0 

73-0 

0.0 

lO.O 

8 

5»4oo 

22.1 

7  5 

67.4 

2.0 

I.O 

9 

5,000 

32.8 

3-6 

55.6 

5-2 

2.8 

10 

4,600 

56.5 

6.0 

34.5 

0.0 

30 

II 

4,100 

530 

6.4 

39.6 

0.0 

I.O 

12 

4,000 

30.0 

14-5 

52.4 

2.0 

I.I 

13 

4,000 

26.8 

15-5 

56.8 

0.9 

0.0 

14 

4,000 

23.0 

16.6 

58.2 

1.2 

I.O 

15 

4,000 

15.0 

50 

77-5 

0.5 

2.0 

16 

4,000 

340 

9.0 

450 

8.0 

4.0 

17 

4,000 

16.3 

8.1 

72.6 

2.0 

I.O 

18 

3,100 

19.7 

23.0 

54.0 

I.O 

2-3 

19 

3,000 

10.8 

20.0 

60.0 

7.2 

2.0 

20 

2,500 

45-0 

12.0 

40.0 

I.O 

2.0 

21 

2,300 

22.1 

16.1 

60.8 

0.0 

I.O 

22 

2,100 

32.1 

21.3 

40.7 

1.6 

4-3 

23 

2,080 

450 

14.7 

38.3 

I.O 

I.O 

24 

2,000 

65.0 

20.0 

14. 1 

0.0 

0.9 

25 

2,000 

145 

14.5 

695 

I.O 

0.5 

26 

1,500 

25.0 

14.0 

61.0 

0.0 

0.0 

27 

1,100 

19. 1 

12. 1 

67.7 

0.3 

o.S 

28 

1,000 

17.0 

21.0 

58.0 

2.0 

2.0 

29 

1,000 

13.0 

II. 0 

72.0 

I.O 

30 

30 

1,000 

20.0 

9.0 

70.0 

0.5 

0.5 

31 

500 

37.5 

18.5 

40.8 

2-3 

0.9 

Av. 

3,925-f 

26+ 

10+ 

58+ 

1+ 

1+ 

.stained  at  all,  the  greater  part  of  the  protoplasm  remaining  an 
indefinite  shade  of  dead  white.  Grmiular  degeneration  of  the 
protoplasm  is  distinctly  evidenced  in  some  of  the  cells,  this  proc- 
ess being  betrayed  by  the  appearance  through  the  stroma  of  the 
affected  cells  of  granular  areas  showing  a  striking  affinity  for  a 
basic  stain  such  as  methylene-blue.     These  basophilic  granules, 


PERNICIOUS    ANEMIA.  2  2/ 

which  have  already  been  described,  are  not  peculiar  to  pernicious 
anemia,  since  they  have  been  found  in  a  large  number  of  secondary 
anemias  of  severe  type,  due  to  various  causes.  (See  page  145.) 
Leucopenia  may  be  counted  on  in  about  three 
Leucocytes,  out  of  every  four  cases  of  pernicious  anemia,  a  fact 
which  stands  in  direct  contrast  to  the  anemias  of 
secondary  type,  in  which  an  increase  in  the  number  of  leucocytes 
is  more  common.  In  an  occasional  case,  especially  in  one  in 
which  the  other  blood  changes  are  inconspicuous,  the  number  of 
leucocytes  is  found  to  be  normal ;  and,  rarely,  a  moderate  leu- 
cocytosis,  attributable  to  some  complication,  exists.  In  the  aver- 
age case,  however,  these  cells  are  distinctly  below  the  normal 
standard,  and  the  degree  of  leucopenia  is  sometimes  extreme, 
the  number  of  cells  occasionally  falling  to  below  1,000  to  the 
cubic  millimeter ;  in  rare  instances,  they  may  apparently  be 
entirely  absent,  none  being  found  after  prolonged  search  both 
through  the  counting  chamber  and  the  stained  film.  In  the  3 1 
cases  collected  in  Table  V.,  the  number  of  leucocytes  averaged 
about  50  per  cent,  of  the  normal  count  (3,925  being  the  exact 
figure),  and  ranged,  in  the  individual  case,  from  500  to  as  high  as 
13,000  to  the  cubic  millimeter.  It  is  interesting  to  note,  in  con- 
nection with  the  preceding  remarks,  that  leucopenia  was  found  in 
22,  or  about  70  per  cent,  of  these  cases. 

The  leucocyte  count,  except  in  the  event  of  complications, 
roughly  parallels  that  of  the  erythrocytes,  falling  coincidently  with 
the  oligocythemia  and  rising  again  as  the  erythrocytes  increase. 
(See  Chart,  p.  222.)  An  exception  to  this  general  rule  is  found  in 
the  terminal  leucocytosis  which  not  uncommonly  develops  just 
before  the  death  of  the  patient. 

Relative  lympJwcytosis  is  a  common,  but  not  a  constant,  find- 
ing in  the  differential  count  of  the  stained  film.  It  seems  to  be 
more  frequently  associated  with  low  than  with  high  counts, 
although  no  hard  and  fast  rule  can  be  laid  down  regarding  this 
point.  In  extremely  leucopenic  blood  a  noteworthy  finding  is 
the  abnormally  high  percentage  of  large  mononuclear  non-gran- 
ular cells,  a  change  which  does  not  ordinarily  take  place  in  con- 
nection with  leucocyte  counts  approaching  the  normal  average. 
The  combined  percentage  of  both  large  and  small  forms  of  lym- 
phocytes in  the  cases  alluded  to  above  (Table  V.)  averaged  37.8, 
individual  counts  varying  from  9.7  to  85  per  cent.  Pre-agonal 
rises  in  the  leucocyte  count  are  sometimes  lymphocytic  in  char- 
acter, resembling  the  blood  changes  seen  in  lymphatic  leukemia, 
and  sometimes  purely  polynuclear  in  type.  The  relative  percent- 
age o{  poly }iticl ear  neittrophiles  averages  low  (58.6  per  cent,  in  the 


228  DISEASES    OF    THE    BLOOD. 

above  series),  but  isolated  counts  show  a  considerable  range  ; 
their  relative  proportion  to  the  other  forms  of  leucocytes  is  largely 
determined  by  the  fluctuations  in  the  percentage  of  lymphocytes. 
The  cosinophilcs  are  almost  invariably  decreased,  and  not  infre- 
quently they  are  wholly  wanting,  a  circumstance  which  was  made 
note  of  in  more  than  1 8  per  cent,  of  the  cases  in  the  present  series, 
in  which  the  average  percentage  of  these  cells  was  1.68.  In  an 
occasional  case  their  percentage  is  abov^e  normal,  as  in  cases  9,  16, 
and  19  in  Table  V. 

In  no  other  disease  save  the  spleno-medullary  form  of  leukemia 
are  myelocytes  so  constantly  found,  but  almost  always  in  relativ^ely 
small  percentages.  In  the  cases  under  consideration  these  cells 
were  absent  in  only  two  instances,  the  average  figure  for  the  3 1 
cases  being  1.82  per  cent.  In  a  single  case  (number  7)  the  re- 
markably high  estimate  (for  this  disease)  of  10  per  cent,  of  myelo- 
cytes was  made,  for  in  the  other  cases  in  which  myelocytes 
occurred  their  percentage  ranged  from  0.4  to  4.3. 

In  the  stained  specimen  it  is  common  to  find  that  the  leuco- 
cytes, particularly  the  polynuclear  neutrophiles,  are  of  smaller 
size  and  more  deeply  stained  than  they  appear  in  normal  blood. 
This  peculiarity  seems  to  be  more  constant  and  more  striking  in 
pernicious  anemia  than  in  any  other  disease,  so  far  as  the  author 
has  been  able  to  determine. 

The  number  of  blood  plaques  is  exceedingly 
Blood         variable,  so  that  it  is  impossible  to  make  definite 
Plaques.       statements  regarding  either  the  increase  or  de- 
crease of  these  bodies.     In  some  cases  they  ap- 
parently are   greatly  increased,  as  evidenced  by  the  groups  of 
a'>-2"lutinated   masses  of  these   cells  which  are    sometimes   seen 
(von  Limbeck^),  but  in  other  cases  it  is  evident  that  their  number 
is  appreciably  diminished  (Hayem  ").     Van  Emden^  supports  the 
latter  view.      In  one  case  this  observer  estimated  their  number  at 
between  32,000  and  64,000  per  cubic  millimeter. 

In    a    typical    case    of    pernicious    anemia    the 

Diagnosis,    blood-picture   upon  which   the  diagnosis  rests  is 
as  follows  : 

Hemoglobin.  Marked  absolute  decrease,  but  of  relatively  higher 
percentage  in  many  cases  than  the  percentage  of 
erythrocytes,  this  giving  rise  to  a  high  color  index. 

Erythrocytes.  Striking  decrease,  commonly  to  1,000,000  or  less 
per  cubic  millimeter.      Counts   of  about   500,000 

^  Loc.  cit. 

2  *'  Legons  sur  les  Maladies  du  Sang,"  Paris,  1900. 

3"Bijd.  t.  d.  ken.  v.  h.  bloed,"  Leiden,  1896. 


PERNICIOUS    ANEMIA. 


229 


are  not  uncommon  during  the  later  stages  of  the 

disease. 

Erythroblasts  constant,  cells  of  the  megaloblastic 

type  predominating. 

Megalocytes  and  microcytes,  the  former  prevailing. 

Poikilocytes,  usually  numerous  and  conspicuous. 

Polychromatophilia, 

BasophiHc  stroma  degeneration  striking  in  severe 

cases. 

Leucocytes.        Usually  decreased ;  decided  leucopenia  common. 
Relative  lymphocytosis  in  the  majority  of  cases. 
Small  numbers  of   myelocytes   almost  invariably 
present. 
Eosinophiles  few,  sometimes  absent. 

Plaques.  Variable. 

Usually  the  diagnosis  of  pernicious  anemia  presents  no  difficul- 
ties, and  may  be  made  by  the  examination  of  the  blood  alone, 
the  association  of  marked  oligocythemia,  a  high  color  index,  leu- 
copenia, and  erythroblasts,  chiefly  of  the  megaloblastic  variety, 
constituting  a  typical  group  of  blood  changes  the  significance  of 
which  is  unmistakable. 

It  should  be  borne  in  mind,  however,  that  these  changes  are 
not  always  present  in  eveiy  case  when  the  patient  first  comes 
under  observation,  so  that  repeated  and  careful  examinations  of 
the  blood  are  sometimes  necessary  before  a  diagnosis  is  possible. 
Of  the  above-named  changes  the  most  important,  from  a  cHnical 
viewpoint,  is  the  prevalence  of  nucleated  erythrocytes  conforming 
to  the  megaloblastic  type.  With  the  two  exceptions  already  noted 
(bothriocephalus  anemia  and  nitrobenzol  poisoning),  this  ''mega- 
loblastic blood-picture"  is  seen  only  in  pernicious  anemia,  and, 
what  is  more  important,  it  occurs  in  every  true  case  of  this  dis- 
ease sooner  or  later  during  its  course.  Inability  to  detect  this 
important  characteristic  should  be  regarded  rather  as  a  reflection 
upon  the  thoroughness  of  the  examiner's  technique  than  as  a 
contradiction  of  the  truth  of  this  statement.  Eiythroblasts  ^me 
not  always  numerous  in  pernicious  anemia,  and  painstaking^avity 
prolonged  study  of  several  stained  films  may  be  necessary  ' 
this  important  feature  is  distinguishable.  general 

In  those  cases  of  doubtful  nature,  in  which  the  typicao-es  the 
changes  are  not  at  once  evident,  a  tentative  diagnosis  as  com- 
made  by  taking  into  careful  consideration  certain  other  )  that  the 
signs  and  symptoms  which  the  patient  presents.  In  v^ally  ap- 
stances  attention  should   be  directed  to  such  suspicious  irade  sec- 


230  DISEASES    OF    THE    BLOOD. 

the  clinical  history  as  the  existence  of  a  severe  anemia  arising 
either  idiopathically  or  without  adequate  cause,  and  pursuing  a 
progressively  unfavorable  course,  uninfluenced  permanently  by 
treatment ;  the  presence  of  a  light  lemon-yellow  tint  of  the  skin, 
of  retinal  hemorrhages,  of  a  peculiarly  soft,  smooth,  flabby  condi- 
tion of  the  skin,  and  sometimes  of  moderate  febrile  paroxysms 
and  gastric  disturbances  ;  and  the  remarkable  preser\^ation  of  the 
patient's  general  nutrition  and  body-weight  in  comparison  with 
the  severity  of  the  illness. 

The  severe  secondary  anemias  due  to  hemorrhage,  to  advanced 
syphilis,  and  to  malignant  disease,  especially  of  the  stomach, 
sometimes  give  rise  to  clinical  symptoms  which  so  exactly  simu- 
late pernicious  anemia  that  the  diagnosis  must  rest  upon  the  re- 
sult of  the  blood  findings,  which  are  usually  well  enough  marked 
to  differentiate  the  conditions.  It  is  true  that  in  these  conditions 
ample  proof  of  sufficient  etiological  factors  for  the  production  of 
the  anemia  is  generally  at  hand,  and  this  fact  should  have  im- 
portant bearing  in  ruling  out  anemia  of  the  pernicious  type,  but 
it  is  also  equally  true  that  in  malignant  disease  it  is  sometimes 
impossible  to  demonstrate  the  lesion,  and  that  in  syphilis  the 
clinical  history  may  be  obscure,  so  that  the  blood  examination 
must,  after  all,  often  be  depended  upon  for  the  detection  of  the 
disease.  In  secondary  anemia  from  the  above  causes  the  oligo- 
cythemia is  seldom  as  excessive  as  it  is  in  pernicious  anemia,  the 
eiythrocytes  rarely  falling  as  low  as  1,000,000  per  cubic  milli- 
meter ;  the  oligochromemia  is  apt  to  be  relatively  greater  than 
the  ohgocythemia,  so  that  a  lower  color  index  results  ;  leucocy- 
tosis  is  not  uncommon  ;  and  while  deformities  of  shape  and  size 
and  nucleation  of  the  erythrocytes  are  frequently  present,  in 
some  instances  to  as  great  an  extent  as  in  pernicious  anemia, 
megalocytes  do  not  predominate,  nor  do  megaloblasts  ever  out- 
number normoblasts. 

From  chlorosis,  which  sometimes  possesses  many  clinical  mani- 
festations in  common  with  pernicious  anemia,  the  diagnosis  may 
usually  be  readily  made  by  the  blood  examination,  which  shows 
decided  differences  between  the  two  diseases.  In  a  typical  case 
of  cliJorosis  the  deterioration  in  the  quality  of  the  blood  affects 
chiefly',  the  hemoglobin  content  of  the  erythrocytes  and  not  the 
cells  tliemselves.  Hence  it  is  common  to  find  m  this  disease 
extreme  oligochromemia  out  of  all  comparison  with  the  more 
moderate  oligocythemia,  and  consequently  a  low  color  index — just 
the  reverse  of  the  condition  found  in  pernicious  anemia.  De- 
formities in  the  shape  and  size  of  the  erythrocytes  are  not  un- 
commor  in  chlorosis,  but  they  are  not  likely  to  be  conspicuous  ; 


SPLENIC    AMEMIA. 


231 


the  prevalent  change  affecting  their  shape  is  microcytosis  of  a 
moderate  grade  of  development,  so  that  a  general  decrease  in  the 
diameter  of  these  cells  is  commonly  observed.  The  most  im- 
portant information  derived  from  the  blood  is,  however,  of  a 
negative  character,  consisting  in  the  fact  that  nucleated  erythro- 
cytes, should  they  be  present,  are  chiefly  normoblasts.  While 
it  is  true  than  an  occasional  megaloblast  may  be  encountered  in 
rare  instances,  no  chlorotic  blood  has  ever  been  known  to  show 
a  predominance  of  this  type  of  cells.  The  behavior  of  the  leuco- 
cytes in  chlorosis  is  of  no  aid  in  the  differentiation  of  this  condi- 
tion from  pernicious  anemia,  for  in  both  diseases  the  count  is 
usually  low  and  relative  lymphocytosis  common  ;  in  the  former, 
however,  the  pronounced  leucopenia  of  the  latter  condition  is  not 
often  found.  Myelocytes,  while  they  may  occur  in  both  diseases, 
are  much  less  common  in  chlorosis. 

In  bothriocephalus  anemia  the  expulsion  of  the  parasite  by  the  ad- 
ministration of  an  appropriate  vermifuge  is  soon  followed  by  a  radical 
change  in  the  blood-picture  and  other  symptoms,  the  megaloblasts 
disappearing,  the  hemoglobin  and  erythrocytes  quickly  rising  to 
the  normal  standard,  and  the  patient's  health  becoming  entirely 
restored.  The  history  of  a  patient  suffering  from  anemia  due  to 
nitrobenzol  poisoning  is  sufficiently  characteristic  to  exclude  true 
pernicious  anemia.  The  differential  diagnosis  between  this  disease 
and  splenic  anemia  is  alluded  to  in  another  place.    (See  page  235.) 

III.     SPLENIC  ANEMIA. 

There  is  nothing  distinctive  about  the  appear- 

Appearance    ance  of  the    drop   of  freshly  drawn    blood,  the 

OF  THE        color  and  density  of  which  varies  with  the  inten- 

Fresh  Blood,  sity  of  the    anemia    present.     The    author    has 

notes  of  a  case  of  splenic  anemia  in  which  it  was 

remarked  that,  from  its  color  and  general  appearance,  the  blood 

drop  resembled   precisely  that  obtained  from  a  typical   case  of 

high-grade  pernicious  anemia  ;  in   a  second  case  the  color  and 

opacity  were  but  slightly  less  than  normal. 

No  reliable  observations  have  thus  far  been  made  regarding 
such  minor  points  as  the  rate  of  coagulation,  the  specific  gravity, 
and  the  reaction  of  the  blood  in  this  form  of  anemia. 

Decided  often  extreme  anemia,  is  the  general 
Hemoglobin    rule  in  this   disease.     In   the  early  stages,  the 
AND  hemoglobin  loss  is   relatively  excessive  as   com- 

Erythrocytes.  pared  to  the  decrease  in  erythrocytes,  so  that  the 
color   index   is    consequently   low — usually  ap- 
proximating the  figures  found  in  many  cases  of  high-grade  sec- 


232 


DISEASES    OF    THE    BLOOD. 


ondary  anemia,  but  not  averaging  so  low  as  in  chlorosis.  As  the 
disease  increases  in  severity,  however,  the  color  index  tends  to 
rise,  as  in  pernicious  anemia,  this  change  being  illustrated  by  the 
counts  tabulated  below. 

In  a  series  of  14  cases  lately  reported  by  Osler,^  the  following 
results  were  obtained  :  the  hemoglobin  in  1 1  cases  averaged 
43.7  per  cent.,  the  lowest  estimate  being  23  and  the  highest  60 
per  cent.  ;  the  erythrocytes  in  10  cases  averaged  3,336,357  per 
cubic  millimeter,  with  extremes  of  2,000,000  and  4,788,000.  In 
a  case  of  splenic  anemia  in  Professor  Hare's  ward  at  the  Jefferson 
Hospital  the  writer  found  the  following  changes,  in  five  consecu- 
tive counts  : 


Date. 

Hemoglobin. 

Color  Index. 

Erythrocytes  per  cb.  mm 

3-  7-98. 

45  per 

cent. 

.82 

2,750,000 

3-14-98. 

40    - 

(I 

•  73 

2,725,000 

3-22-98. 

43    '' 

11 

.76 

2,812,000 

3-29-98. 

45    " 

(( 

.69 

3,275,000 

4-1 1-98. 

40    '' 

(( 

I. 00 

2,000,000 

Deformities  affecting  the  size  of  the  erythrocytes,  sometimes 
tending  toward  striking  megalocytosis,  may  be  met  with  in  cases 
characterized  by  great  oligocythemia,  such  an  alteration  being  also 
associated  with  a  greater  or  less  degree  of  poikilocytosis,  and  with 
signs  of  stroma  degeneration.  Nucleated  erythrocytes,  although 
they  occur  infrequently,  may  be  present  in  enormous  numbers  in 
severe  cases,  creating  a  blood-picture  which  is  distinguishable 
from  that  of  true  pernicious  anemia  only  by  the  fact  that  normo- 
blasts predominate.  Thus,  in  one  of  McCrae's  counts  in  a  case 
of  Osier's,  in  which  the  hemoglobin  was  reduced  to  20  and  the 
erythrocytes  to  27.6  per  cent.,  no  fewer  than  75  erythroblasts 
(of  which  21  were  normoblasts,  19  megaloblasts,  and  35  "inter- 
mediate "  forms)  were  seen  while  counting  400  leucocytes.  In 
the  case  above  summarized  the  average  number  of  erythroblasts 
per  1,000  leucocytes  was  estimated  as  6y  (the  maximum  and 
minimum  being  128  and  9,  respectively)  for  the  five  examinations, 
41  of  these  cells  being  normoblasts,  and  26  megaloblasts.  The 
presence  of  nucleated  erythrocytes  in  such  large  numbers  as  were 
found  in  these  two  instances  must,  however,  be  regarded  as  most 
exceptional.  Polychromatophilic  staining  of  many  of  the  erythro- 
cytes may  be  a  striking  feature  in  advanced  cases,  but  in  those  of 
a  milder  grade  the  phenomenon  is  absent.  Absence  of  basophilic 
granular  degeneration  of  the  cells  has  been  noted  by  Cohn.^ 

^  Am.  Joum.  of  Med.  Sc,  1900,  vol.  cxix.,  p.  54. 
2Munch.  med.  Woch.,   1900,  vol.  xlvii.,p.  618. 


SPLENIC    ANEMIA.  233 

Leucopenia,  sometimes  pronounced,  is  found  in 
Leucocytes,  the  great  majority  of  cases,  counts  of  from  2,000 
to  4,000  cells  to  the  cubic  millimeter  being  com- 
mon ;  as  in  pernicious  anemia,  the  lowest  leucocyte  counts  are 
generally  associated  with  those  cases  in  which  the  anemia  is  most 
intense.  Leucocytosis  occurs  only  as  the  effect  of  some  compli- 
cation, and  therefore  is  but  occasionally  encountered.  In  Osier's 
series,  above  referred  to,  the  number  of  leucocytes,  determined  in 
13  cases,  averaged  4,770  per  cubic  millimeter,  ranging  from 
2,000  to  12,497,  the  latter  estimate  being  the  only  one  exceeding 
10,000;  in  9  of  the  cases  the  count  fell  below  5,000.  In  the 
writer's  case  the  five  counts  averaged  2,400,  varying  from  1,000 

to  4,000. 

No  constant  differential  changes  have  been  observed,  but  rela- 
tive lymphocytosis  is  not  infrequent,  sometimes  involving  chiefly 
the  large,  and  sometimes  the  small  forms  of  these  cells.  The  pro- 
portion of  both  combined  may  be  as  high  as  50  or  60  per  cent., 
an  increase  of  this  kind  bringing  about  a  consequent  fall  in  the 
relative  percentage  of  polymiclear  neiitrophiles.  Small  numbers 
of  7nyelocytes,  rarely  in  excess  of  a  fraction  of  one  per  cent., 
are  to  be  expected  in  cases  with  decided  oligocythemia.  The 
eosinophiles  remain  at  about  the  normal  standard.  Typical 
coarsely-granular  mast  cells  are  sometimes  found  in  relatively 
large  numbers — as  high  as  5  or  6  per  cent,  of  all  forms  of 
leucocytes. 

No  special  observations  concerning  the  behavior  of  the  blood 
plaques  in  this  disease  have  been  recorded  up  to  the  present  time. 
It  is  evident,  however,  that  they  are  not  notably  increased  in 
number. 

To  recapitulate,  the  blood  changes  which  have 
Diagnosis,     been    most   frequently   found   in    splenic    anemia 
may  be  tabulated  as  follows : 

Hemoglobiit.      Marked  diminution  ;  color  index  variable. 

Erythrocytes.     Usually    reduced    moderately,   sometimes    exces- 
sively.    Counts  between  3,000,000  and  4,000,000 
cells  per  cubic  millimeter  are  most  common. 
Deformities  of  shape,  especially  megalocytosis,  and 
poikilocytosis  common  in  advanced  cases. 
Erythroblasts  rare,  except  in  cases  with  decided 
oligocythemia.      Normoblasts  invariably  predomi- 
nate. 
Polychromatophilia  in  severe  cases. 


234  DISEASES    OF    THE    BLOOD. 

Leucocytes.         Leucopenia  the  general  rule. 

Relative  lymphocytosis  common. 

Small  numbers  of  myelocytes  in  advanced  cases. 

Relatively    large  percentages    of   mast  cells    not 

uncommon. 

Eosinophiles  normal. 

Plaques.  Not  increased. 

Many  writers  still  hesitate  to  assign  to  splenic  anemia  the  role 
of  a  definite  clinical  entity,  choosing  to  regard  the  condition 
either  as  a  splenic  form  of  Hodgkin's  disease,  or  as  high-grade 
secondary  anemia  with  marked  splenic  hyperplasia.  But  of  late 
the  majority  of  observers,  especially  those  of  the  British  school, 
lean  toward  at  least  a  tentative  recognition  of  the  condition  as  a 
distinct  although  an  obscure  disease.^  Osier ^  well  expresses 
the  consensus  of  opinion  when  he  remarks  that  "  provisionally, 
until  we  have  further  knowledge,  it  is  useful  to  group  together 
.  .  .  cases  of  idiopathic  enlargement  of  the  spleen  with  anemia 
without  lymphatic  involvement,  and  to  label  the  condition  splenic 
anemia." 

It  is  quite  obvious,  from  a  glance  at  the  above  synopsis  of  the 
blood  condition,  that  splenic  anemia  presents  no  characteristic 
blood-picture  by  which  the  diagnosis  can  be  made,  so  that  in 
order  to  differentiate  it  from  a  number  of  other  diseases  which  it 
more  or  less  closely  simulates,  careful  study  of  other  cHnical 
features  is  essential. 

The  onset  of  splenic  anemia  is  gradual  and  insidious,  its  course 
is  prolonged  often  for  a  number  of  years,  and  its  termination  is 
ultimately  fatal.  The  principal  clinical  features  are  the  leuco- 
penic  anemia,  the  great  splenic  tumor,  and  the  absence  of  all  en- 
largement of  the  superficial  lymphatics.  In  some  instances  the 
anemia  develops  in  advance  of  the  splenic  tumor,  but  it  is  more 
often  the  case  that  the  enlargement  of  the  spleen  is  the  earliest 
demonstrable  lesion.  The  anemia  is  responsible  for  such  symp- 
toms as  dyspnea,  vertigo,  cardiac  palpitation,  loss  of  strength 
and  appetite,  and  the  occurrence  of  unexplained,  irregular  periods 
of  fever  ;  and  for  such  signs  as  hemic  heart  murmurs,  pallor, 
lemon-yellow  discoloration  of  the  skin  and  mucous  membranes, 
and  sometimes  pigmentation  of  the  skin.  The  enlarged  spleen 
may  extend  as  far  down  as  the  umbilicus,  and  sometimes  far  be- 
low this  point,  even  to  the  iliac  crests  ;  the  surface  of  the  organ 

'For  a   critical  resume  of  the  literature  on  splenic  anemia,  Sippy's  article  in  the 
American  Journal  of  Medical  Sciences,  1899,  vol.  cxviii.,  p.  570,  should  be  consulted. 
^  Loc.  cit. 


SPLENIC    ANEMIA.  235 

is  smooth  and  free  from  nodules,  its  consistence  is  firm,  and  its 
shape  is  unaltered.  It  may  give  rise  to  no  symptoms,  but  occa- 
sionally it  is  the  cause  of  great  pain  and  of  hematemesis,  the  latter 
being  due  to  simple  mechanical  congestion.  Epistaxis,  purpura, 
and  hematuria  have  also  been  obsei-ved.  Ascites  sometimes  de- 
velops, as  the  result  either  of  the  splenic  enlargement,  or  of  the 
anemia.  Enlargement  of  the  liver,  usually  associated  with  ca- 
tarrhal jaundice,  occurs  in  a  large  proportion  of  cases,  and  such 
gastro-intestinal  disturbances  as  anorexia,  nausea,  vomiting,  and 
both  constipation  and  diarrhea  are  extremely  common.  Splenic 
anemia  may  prove  fatal  within  six  months  after  the  onset  of  the 
initial  symptoms,  or  it  may  drag  along  for  as  many  years,  but,  as 
a  general  rule,  its  duration  does  not  exceed  two  or  three  years. 
In  one  of  Osier's  cases  the  condition  probably  lasted  for  at  least 
twelve  years,  and  in  a  case  now  under  treatment  in  the  Jefferson 
Hospital  the  splenic  tumor  and  the  anemia  have  existed  for  the 
last  six  years,  if  not  longer.  As  in  pernicious  anemia,  periods  of 
remission  during  which  the  leading  symptoms  disappear  and  the 
quality  of  the  blood  improves,  are  commonly  observed  in  this 
condition. 

The  spleno-medullary  form  of  leukemia,  pernicious  anemia,  and 
Hodgkin's  disease  with  splenic  ejtlargemeiit  all  present  clinical 
features  counterfeiting  more  or  less  faithfully  splenic  anemia,  but 
the  differential  diagnosis  between  these  conditions  does  not  in- 
volve any  great  difficulty.  The  result  of  the  blood  examination 
gives  the  clue  to  the  two  diseases  first  named,  the  myelocytic 
type  of  blood  in  leukemia,  and  the  predominance  of  megaloblasts 
in  pernicious  anemia  being  sufficient  to  fix  the  identity  of  these 
conditions.  In  Hodgkin's  disease  with  enlargement  of  the  spleen 
there  is  more  or  less  marked  enlargement  of  the  superficial 
lymphatic  glands,  and  the  splenic  tumor  rarely  attains  the  size 
to  which  that  organ  grows  in  splenic  anemia ;  the  blood-picture 
of  the  two  conditions,  it  must  be  recalled,  may  be  identical. 

Enlargements  of  the  spleen  due  to  such  factors  as  chronic  ma- 
larial iitfection,  amyloid  disease,  malignant  g7'owths,  echinococcus 
cysts,  and  hepatic  cirrhosis  also  occasionally  require  differentiation 
from  splenic  anemia.  A  history  of  previous  attacks  of  malarial 
fever,  and  the  detection  of  the  specific  parasite  or  of  pigment  in 
the  blood  will  serve  to  distinguish  tumors  of  the  spleen  of  malarial 
nature.  In  amyloid  disease  a  histoiy  of  long-standing  suppura- 
tion, of  tuberculosis,  or  of  syphilis,  and  the  presence  of  signs  in- 
dicating amyloid  degeneration  of  other  organs,  notably  the  liver, 
kidneys,  and  intestines,  are  the  chief  differentiating  features.  In 
malignant  disease  of  the  spleen  the  tumor  is   uneven,  irregular, 


236  DISK\SES    OF    THE    BLOOD. 

and  nodular,  evidences  elsewhere  of  malignant  lesions  generally 
exist,  and  a  well-defined  leucocytosis  is  common.  Echino- 
coccus  disease  of  the  spleen  pursues  a  protracted  course  unac- 
companied by  signs  of  anemia,  and,  unless  secondar\^  infection 
takes  place,  unassociated  with  rises  in  temperature ;  fluctuation  of 
the  tumor  can  frequently  be  detected ;  and  booklets  can  be  recog- 
nized in  the  fluid  obtained  from  the  organ  by  aspiration.  In 
splenic  enlargements  associated  with  the  different  varieties  of 
hepatic  cirrhosis,  the  previous  history^  and  the  cachexia  of  the 
patient,  the  relatively  moderate  size  of  the  tumor,  the  signs  of 
portal  congestion,  the  condition  of  the  liver,  and  the  course  of 
the  disease  should  be  taken  into  account. 


IV.     SECONDARY  ANEMIA. 

An   approximate  idea  of  the  intensity^  of  the 
Appearanxe    anemia  may  usually  be  formed  by  noting    the 
OF  THE         gross  appearance  of  the  fresh  blood  drop,  but  it 
Fresh  Blood,  must  be   remembered  that  it  is   only  when  the 
process  has  reached  a  comparatively  high  grade 
of  development  that  the  fact  is  betrayed  by  any  marked  devia- 
tion from  normal  in  the  color  and  densitv  of  the  blood.      In  the 
average  case  of  well-marked  secondary  anemia  the  color  of  the 
drop  is  but  slightly  paler  than  normal,  if,  indeed,  it  is  visibly  al- 
tered ;  but  if  the  anemia  is  of  decided  severity  it  may  resemble  a 
thin,  serum-colored  liquid  streaked  with  crimson,  similar  to  the 
water}^  blood  drop  of  typical  pernicious  anemia.      In  such  cases 
microscopical  examination  of  the  fresh  film  shows  that  there  is 
little  or  no  tendency  toward  rouleaux  formation. 

In  general  terms,  it  may  be  stated  that  the 
Coagulation,  rapidity  of  coagulation  bears  a  direct  relation 
to  the  grade  of  the  anemia,  since  it  has  been 
determined  that  the  greater  the  oligochromemia  and  oligocy- 
themia, the  more  rapid  the  process  of  clotting.  In  secondary^ 
anemias  with  ervthrocvte  counts  under  i  ,000,000  Lenoble  ^ 
found  that  coagulation  was,  as  a  rule,  at  least  twice  as  rapid  as 
normal. 

The  specific  gravity  of  the  whole  blood  is  re- 

Specific       duced,  a  change  which  is  dependent  chiefly  upon 

Gravity.       the  loss  of  hemoglobin.     Sufficient  reference  has 

already  been  made  to  this  subject  in  a  previous 

section.     (See  page  98.) 

^  Lx)c.  cit. 


SECONDARY   ANEMIA.  237 

The  majority  of  authors  maintain  that  the  al- 
Alkalinity.  kalinity  of  the  blood  is  decreased  in  relation  to 
the  degree  of  the  anemia,  and  a  large  number  of 
experiments  in  anemias  due  to  various  factors  apparently  justify 
this  general  belief.  But  several  careful  investigators,  notable 
among  whom  is  Lowy,^  have  contradicted  these  reports,  having 
found  the  alkalinity  normal  or  even  above  normal  in  numerous 
cases.  The  author  quoted,  for  example,  calculated  the  alkalinity 
in  various  cases  of  secondary  anemia  at  from  360  to  675  mgrms., 
as  compared  with  his  normal  standard,  447  to  508  mgrms. 

Taking   the  ordinarily  well-developed  case  of 
Hemoglobin    secondary  anemia  as  an  example,  it  is  found  that 
AND  the  hemoglobin  percentage  and  number  of  erythro- 

Erythrocytes.  cytes  are  both  decidedly,  though  not  strikingly, 
diminished.  As  the  former  usually  shows  a  dis- 
proportionately greater  loss  than  the  latter,  subnormal  color  in- 
dices are  the  rule,  ranging,  say,  from  about  0.75  to  0.85.  In 
anemias  of  severer  type,  such  as  those  due  to  gastric  cancer  and 
to  enteric  fever,  the  losses  frequently  are  much  more  exaggerated, 
and,  in  so  far  as  the  purely  quantitative  changes  in  the  erythro- 
cytes and  their  hemoglobin  equivalent  are  concerned,  the  blood 
picture  of  true  pernicious  anemia  may  be  counterfeited.  In  the 
anemias  of  syphilis,  of  tuberculosis,  and  of  malignant  disease  in 
general  the  disproportionate  hemoglobin  loss  may  be  so  decided 
that  the  blood  changes  cannot  be  distinguished  from  those  of 
chlorosis,  and  to  this  condition  the  much-abused  term  ''  chloro- 
anemia  "  has  been  applied. 

The  fact  must  be  emphasized  that  simply,  the  hemoglobin  esti- 
mate and  erythrocyte  count  alone  are  absolutely  uncharacter- 
istic in  secondary  anemias,  for  they  may  range  in  the  individual 
case  from  slightly  subnormal  figures  to  an  extreme  degree  of 
oligochromemia  and  oligocythemia.  In  a  patient  studied  by 
von  Limbeck,-  for  example,  at  one  time  the  erythrocytes  num- 
bered only  306,000  per  cubic  millimeter,  but  ultimately  perfect 
recovery  ensued  and  the  count  rose  to  4,280,000.  But  if  aver- 
ages are  used  as  a  basis  for  conclusions,  it  becomes  evident  that 
the  hemoglobin  diminution  is  less  marked  than  in  any  other  blood 
disease,  and  that  the  erythrocyte  loss  is  also  less  than  in  any 
other  form  of  anemia  except  chlorosis.  Data  based  upon  200 
examinations  of  various  types  of  anemia  by  the  writer  give  the 
following  results  regarding  these  points  : 

^Centralbl.  f,  d.  med.  Wissensch.,  1894,  vol.  xxxii.,  p.  785. 
2Loc.  cit. 


238 


DISEASES    OF    THE    BLOOD. 


Disease. 

Average  Percentage  of  Hemo- 
globin Loss  in  50  Consecu- 
tive Estimates. 

Average  Percentage  of  Ery- 
throcj'te  Loss  in  50  Con- 
secutive Counts. 

Secondary  Anemia. 
Chlorosis. 
Leukemia. 
Pernicious  Anemia. 

44.8  per  cent. 
54.8       - 
60.6       " 

74.5       " 

27.1  per  cent. 
17.8 

45-4 
76.9          " 

Examination  of  the  stained  specimen  shows  a  variable  degree 
of  alteration  in  the  shape,  size,  and  general  structure  of  the  cells. 
In  mild  cases  simple  pallor  of  the  erythrocytes,  with  perhaps  a 
few  microcytes  and  moderately  misshapen  poikilocytes  are  the 
only  changes  to  be  observed,  erythroblasts,  polychromatophiles, 
and  cells  with  basophilic  stroma  degeneration  being  entirely 
wanting.  In  severe  cases,  with  excessive  oligocythemia,  a  large 
proportion  of  the  cells  are  either  under-  or  over-sized,  the  latter 
forms  appearing  to  prevail  in  relation  to  the  intensity  of  the  ane- 
mic process  ;  poikilocytosis  and  polychromatophilia  are  sometimes 
extreme,  and  evidences  of  Grawitz's  stroma  degeneration  are 
found,  together  with  a  more  or  less  abundance  of  nucleated  eryth- 
rocytes, the  majority  of  which  conform  to  the  normoblastic 
type.  In  most  instances  normoblasts  only  are  present,  but  rarely 
an  occasional  megaloblast,  implying  a  slight  tendency  toward  a 
fetal  type  of  hemogenesis,  is  also  seen.  The  significance  of 
erythroblasts  in  anemia  and  the  circumstances  under  which  they 
are  found  have  been  discussed  in  a  preceding  section.      (See  page 

141.) 

Typical  polynuclear  neutrophile  leucocytosis 
Leucocytes,  is  common  but  by  no  means  constant  in  the  sec- 
ondar}'  anemias,  independent  of  their  grade,  for 
the  cellular  increase  is  provoked  by  a  stimulation  of  the  functional 
activities  of  the  marrow,  which  vary  according  to  the  individual 
and  to  the  nature  of  the  exciting  cause.  The  differential  changes 
associated  with  such  a  leucocytosis  (low  percentages  of  lympho- 
cytes and  eosinophiles,  with,  perhaps,  a  few  myelocytes)  have 
already  been  referred  to  in  a  preceding  section.  A  moderate 
leucocytosis  is  especially  common  in  the  anemias  of  children, 
and  in  those  symptomatic  of  inflammatory  and  suppurative  condi- 
tions and  of  malignant  diseases.  While  in  other  anemias,  espe- 
cially those  of  chronic  type,  a  normal  leucocyte  count  or  even 
leucopenia  may  be  found,  often  in  association  with  a  relative 
lymphoc>'tosis,  as  is  frequently  the  case  in  the  anemias  of  enteric 
fever  and  of  tertiary  syphilis. 


POST-HEMORRHAGIC    ANEMIA.  239 

The  plaques  are  usually  increased,  but  appa- 
Blood         rently  without  any  constant  relationship  to  the 
Plaques.       degree  of  hemoglobin  and  erythrocyte  loss.     In 
some  cases  these  bodies  may  number  more  than 
double  the  maximum  normal  standard,  as  in  a  case  of  anemia  in 
a  child  with  a  tumor  of  the  spleen,  noted  by  von  Emden,^  in  which 
an  estimate  of  829,000  to  the  cubic  millimeter  was  made. 
Diagnosis  principal  blood  changes  found  in  second- 

ary anemia  are  as  follows  : 

Hemoglobin.     Variable  decrease,  usually  somewhat  more  marked 
than  the  erythrocyte  loss  ;  color  index  subnormal. 

Erythrocytes.     Variable  decrease. 

Erythroblasts,  in  severe  cases;  normoblasts  out- 
numbering megaloblasts,  which  are  rare. 
Deformities  of  shape  and  size,  polychromatophilia, 
and  basic  staining  of  the  stroma  in  severe  cases. 

Leucocytes.         Commonly  increased  ;  rarely  leucopenia. 

Polynuclear  neutrophiles  usually  increased,  and 
lymphocytes  and  eosinophiles  relatively  dimin- 
ished. 

Lymphocytosis  in   some   cases,  usually  those   of 
severe  type  and  chronic  course. 
Small  numbers  of  myelocytes  sometimes  found. 

Plaques.  Usually  increased. 


V.     POST-HEMORRHAGIC   ANEMIA. 

Among  the  many  underlying  causes  of  acute 
Etiology,  post-hemorrhagic  anemias  may  be  mentioned 
trauma,  abortion,  post-partum  hemorrhage,  epis- 
taxis,  pulmonary  tuberculosis,  peptic  ulcer,  enteric  fever,  visceral 
carci7ioma,  hemorrhagic  pancreatitis,  and  the  rupture  of  an  aneu- 
rysm, of  a  Fallopian  tube  during  ectopic  pregnancy,  and  of  a  mass 
of  extensively  varicose  veins.  Chronic  hemorrhages  resulting, 
for  example,  from  diseases  belonging  to  the  hemorrhagic  diathesis, 
from  hemorrhoids,  or  from  uterine  diseases  usually  give  rise  to  a 
much  less  decided  blood  loss  than  the  first-named  conditions,  but 
in  some  instances  these  factors,  if  persistent,  may  be  sufficient  to 
provoke  eventually  a  high-grade  anemia. 

^  Loc.  cit. 


240  DISEASES    OF    THE    BLOOD. 

Reduction  in  the  total  volume  of  blood,  or 
Effect  Upon  oligcinia,  ensues  as  the  immediate  effect  of  an 
THE  Blood,  acute  hemorrhage,  and  a  count  made  immedi- 
ately after  the  blood  loss  may  show  no  reduction 
in  the  hemoglobin  and  corpuscular  value,  since  the  oligemia  af- 
fects the  liquid  and  cellular  elements  proportionately.  As  reac- 
tion sets  in,  the  system  attempts  to  compensate  for  the  loss  of 
blood,  by  the  rapid  absorption  by  the  capillaries  of  large  amounts 
of  liquids  from  the  tissues,  so  that  the  blood  soon  becomes  highly 
diluted,  or  hydremic.  This  is  evidenced  by  a  proportionate  dimi- 
nution in  the  hemoglobin  paxentagc  and  tiytJirocyte  count,  the 
degree  of  this  decrease  depending  upon  the  extent  of  the  hem- 
orrhage. It  is  thought  that  in  many  instances  this  fluid  transfer 
from  tissue  to  vessel  is  inaugurated  immediately  after  or  even 
during  the  hemorrhage,  and  that  the  original  volume  of  blood  is 
restored  within  a  few  hours.  A  further  diminution  in  hemo- 
globin and  erythrocytes  occurs  after  the  normal  volume  of  blood 
has  been  reestablished,  so  that  the  minimum  decrease  is  not  ob- 
served until  some  little  time  has  elapsed  after  the  hemorrhage. 
As  a  rule,  the  minimum  count  is  seen  at  some  period  during  the 
first  week  after  the  blood  loss,  as  early  as  the  first  or  second  day 
in  some  instances,  but  as  late  as  the  tenth  or  eleventh  day  in 
others.  This  secondary  fall  is  thought  to  depend  upon  the  in- 
troduction into  the  circulation  of  large  numbers  of  immature, 
feebly  resistant  erythrocytes,  which  suffer  rapid  and  premature 
destruction,  and  thus  bring  about  a  disturbance  in  the  equilibrium 
between  the  rate  of  blood  production  and  blood  destruction  in 
favor  of  the  latter.  As  soon  as  the  marrow  is  able  to  meet  the 
drain  in  an  adequate  manner,  by  the  increased  production  of  more 
resistant  cells,  the  anemia  ceases,  and  the  hemoglobin  and  eryth- 
rocyte estimates  begin  to  rise. 

Authorities  differ  as  to  the  degree  of  blood  loss  which  man  is 
capable  of  surviving,  a  difference  which  is  but  natural' when  it  is 
remembered  that  factors  other  than  the  actual  amount  of  blood 
lost,  conspicuous  among  which  are  the  age,  sex,  and  resisting 
powers  of  the  patient,  are  all  important  in  determining  the  fatality 
of  the  hemorrhage.  According  to  Immermann,^  hemorrhages 
involving  a  loss  of  one-half  of  the  total  bulk  of  blood  in  the 
body  invariably  prove  fatal.  Hayem '"  is  authority  for  the  state- 
ment that,  as  a  general  rule,  recovery  is  possible  when  the  total 
volume  of  blood  lost  does  not  exceed  y^th  of  the  individual's 
body-weight.     This  author  has   reported  the  most  astonishing 

^  Cited  by  Rieder,  loc.  cit. 
2Loc.  cit. 


POST-HEMORRHAGIC    ANEMIA.  24 1 

example  on  record  of  post-hemorrhagic  cellular  decrease,  in 
which  he  observed  a  diminution  in  the  erythrocytes  to  1 1  per 
cent,  of  normal,  in  a  case  of  post-partum  hemorrhage,  with  sub- 
sequent recovery  of  the  patient.  Behier  ^  has  described  a  case 
of  metrorrhagia  in  which  recovery  occurred,  in  spite  of  a  reduc- 
tion in  the  erythrocytes  to  19  per  cent,  of  normal.  Laache^  has 
recorded  a  number  of  instances  in  which  the  corpuscular  esti- 
mates fell  below  50  per  cent,  of  normal,  in  one  case  to  32  per  cent. 
These  last  three  examples  are  sufficient  to  disprove  the  former 
belief,  that  death  inevitably  ensues  when  the  corpuscular  loss,  as 
the  result  of  hemorrhage,  falls  as  low  as  50  per  cent,  of  normal. 

Increase  in  the  number  of  leucocytes,  usually  of  moderate  de- 
gree, promptly  develops  in  the  great  majority  of  cases,  and  per- 
sists for  several  days.  It  usually  involves  an  absolute  and  rela- 
tive gain  in  the  polynuclear  neutrophile  cells  with  a  consequent 
decrease  in  the  mononuclear  forms,  but,  rarely,  the  reverse  may 
be  noted.     In  fatal  cases  this  increase  may  not  occur. 

The  maximum  count  is  commonly  attained  within  a  few  hours 
after  the  onset  of  the  leucocytosis.  (See  *'  Post-hemorrhagic 
Leucocytosis,"  page  191.) 

According  to  most  authors,  the  blood  plaques  are  strikingly  in- 
creased after  hemorrhage.  The  coagulability  of  the  blood  is  ab- 
normally quick,  being  more  rapid  in  profuse  than  in  moderate 
hemorrhages. 

Following  the  reestablishment  of  the  normal 

Regenera-     blood  volume,  regeneration  of  the  erythrocytes 
TiON.  and  hemoglobin,  and  a  consequent  dissipation  of 

the  hydremia,  ensues.  The  time  necessary  for 
the  completion  of  this  process  varies  greatly  in  different  individ- 
uals, as  the  rapidity  with  which  blood  regeneration  occurs  depends 
upon  different  factors,  such  as  the  extent  of  the  original  hemor- 
rhage, and  the  age  and  natural  regenerative  powers  of  the  patient. 
The  latter  are  at  their  maximum  during  the  third  and  fourth 
decades  of  life,  at  their  minimum  during  infancy  and  old  age,  and 
are  regarded  as  more  active  in  women  than  in  men.  The  exist- 
ence of  a  well  developed  cachexia,  or  an  infectious  disease,  as 
well  as  the  neglect  of  proper  treatment  of  the  hemorrhage,  are 
obstacles  which  retard  the  regeneration  of  the  blood  to  its  normal 
composition.  The  process  appears  to  be  more  active  if  trans- 
fusion of  a  normal  saline  solution  has  been  practised  than  in  un- 
treated cases,  the  rapidity  of  the  gain  being  especially  striking 
during  the  latter  half  of  the  regeneration  period.     The  transfusion 

1  Cited  by  Laache,  loc.  cit. 
*'*Die  Anemie,"  Christiania,  i 

16 


242  DISEASES    OF    THE    BLOOD. 

of  blood  hastens  regeneration  even  more  decidedly.  Otto/  and 
Hall  and  Eubank  -  have  shown  experimentally  in  animals,  bled 
and  given  transfusions  of  artificial  serum,  that  regeneration  once 
stimulated  into  activity  may  carry  the  blood,  quantitativ^ely,  con- 
siderably beyond  the  established  normal  standard. 

In  uncomplicated  cases,  according  to  Bieifreund,^  regeneration  is 
effected  within  about  four  weeks  if  the  hemorrhage  produces  a  hem- 
oglobin loss  of  25  per  cent.,  and  in  about  three  weeks  if  the  loss 
does  not  exceed  20  per  cent.  The  latter  period  may  be  regarded 
as  the  average  regeneration  time  in  the  great  majority  of  instances. 

As  regeneration  proceeds,  the  hemoglobin  and  corpuscular 
deficiencies  gradually  become  less  conspicuous,  but  the  increase 
in  these  two  constituents  does  not  occur  along  parallel  lines. 
The  increase  in  the  number  of  erythrocytes  is  much  more  rapid 
than  the  gain  in  the  hemoglobin  percentage,  and  the  latter  usually 
remains  subnormal  for  some  time  after  the  normal  number  of 
corpuscles  has  been  reestablished.  Owing  to  this  lagging  behind 
of  the  hemoglobin,  low  color  indices  are  the  rule.  Faulty 
hemogenesis,  owing  to  which  the  great  majority  of  the  erythro- 
cytes are  deficient  in  hemoglobin  and  many  of  them  of  abnormally 
small  size,  serves  best  to  explain  this  slow  restitution  of  the  hemo- 
globin value. 

The  appearance  in  the  blood  of  normoblasts  is  common  after 
hemorrhage,  and  in  rare  instances  an  occasional  megaloblast  and 
atypical  forms  of  erythroblasts  may  be  observed.  According  to 
Ehrlich,"*  if  thorough  and  systematic  search  is  made,  normoblasts 
may  be  constantly  found  after  the  second  or  third  day  following 
the  blood  loss  until  the  regeneration  of  the  blood  is  complete. 
The  transient  appearance  of  large  numbers  of  normoblasts,  know^n 
as  "  blood  crises,"  has  been  already  described.  (See  page  143.) 
Dawson,^  who  has  carefully  studied  the  effects  of  venous 
hemorrhage  in  dogs,  found  no  evidence  of  any  close  relation 
between  the  number  of  eiythroblasts  and  the  rapidity  and  char- 
acter of  the  regeneration  of  the  hemoglobin  and  erythrocytes. 
In  severe  cases  polychromatophilia  of  the  erythrocytes  may  be 
noted,  this  sign  first  becoming  apparent  as  early  as  the  first  day 
after  the  hemorrhage,  and  gradually  disappearing  as  regenera- 
tion is  effected.  Deformities  in  the  size  and  shape  of  the  erythro- 
cytes are  not  uncommon,  of  which  microcytes  constitute  the  most 
frequent  example.  Large  hydropic  macrocytes  and  poikilocytes 
are  met  with  more  rarely. 

^Pfliiger's  Archiv.,  1885,  vol.  xxxv.,  p.  57. 
2Journ.  of  Exp.  Med.,  1896,  vol.  i.,  p.  656. 
3  Langenbeck's  Archiv.,  1890-91,  vol.  xli.,  p.  i. 
*Loc.  cit. 
5  Amer.  Jour,  of  Physiol.,  1900,  vol.  iv.,  p.  2. 


a 
z 
< 
> 

z 

o 
u 
a 

CD 

Moderate  or  marked  de- 
crease. 

Relatively  low  or  propor- 
tionate to  erythrocyte  loss. 

Moderate  or  excessive 
decrease. 

Pallor  slight  or  marked. 

Poikilocytosis  variable. 

Erythroblasts  in  severe 
cases,   normoblasts   pre- 
lominating.  ^ 

Polychromatophila  and 
basophilic  stroma  degen- 
ert.'^ion  in  severe  cases. 

Cl  anges  in  diameter  of 
cells  variable. 

Subnormal,  sometimes 
very  low. ' 

Usually  increased 
moderately. 

Polynuclcc  '     neutrophile 
increase   witl    lymphocyte 
decrease  comi  'on. 

Eosinophiles  usually 
decreased  or  ab.-;ent. 

Small  numbers  of  myelo- 
cytes in  severe  cas.^s. 

Basophiles  not  increased. 

t5 

in 

03 
<U 

in 
CJ 

.a 
>^ 

'^ 

is 

<: 

u 

z 
w 

Marked  decrease,  aver- 
aging to  about  45  per  cent. 

Relatively  low  or  high  to 
erythrocyte  loss. 

Decided  decrease,  coun  s 
averaging  about  3,500,000. 

Pallor  variable. 

Poikilocytosis    in    severe , 
cases. 

Erythroblasts    rare,    nor- 
moblasts predominating. 

Polychromatophilia   vari- 
able ;  basophilic  stroma 
degeneration  absent. 

Changes  in  diameter  of 
cells  inconstant. 

Moderately   low,  averag- 
ing about  0.75. 

Normal  or  decreased, 
counts  averaging  about 
5,000. 

Relative      lymphocytosis 
and  decrease  of  polynuclear 
neutrophiles  frequent. 

Eosinophiles  normal. 

Myelocytes  rare. 

Basophiles  sometimes 
increased. 

<v 
tn 

CS 

c 

< 

S 
u 

< 

o 

M 

u 

Striking  decrease,  aver- 
aging to  about  25  per  cent. 

Relatively  high  to  eryth- 
rocyte loss. 

Excessive  decrease, 
counts  averaging  about 
1,250,000, 

Pallor  not  marked. 

Poikilocytosis  usually 
conspicuous. 

Erythroblasts      constant, 
megaloblasts     predominat- 
ing. 

Polychromatophilia     and 
basophilic  stroma  degener- 
ation common. 

Megalocytosis  common. 

High,  averaging  i.oo 
plus. 

Decreased,   counts   aver- 
aging about  4,000. 

Relative  lymphocytosis 
and  decrease  of  polynuclear 
neutrophiles  the  rule. 

Eosinophiles  often  absent, 
usually  much  decreased. 

Myelocytes  in  small 
numbers  almost  constant. 

Basophiles  not  increased. 

> 

52 

O 

» 

o 
X 

u 

Marked  decrease,  aver- 
aging to  about  50  per  cent. 

Relatively  low  to  eryth- 
rocyte loss. 

Moderate  decrease,  counts 
averaging  about  4,000,000. 

Pallor  conspicuous. 

Poikilocytosis  rarely 
marked. 

Erythroblasts  rare,  normo- 
blasts predominating. 

Polychromatophilia  rare ; 
basophilic  stroma  degenera- 
tion absent. 

Microcytosis  common. 

bjo 
C 

'So 

)-l 

0  "^ 

^1 

Normal  or  decreased, 
counts  averaging  about 
7,000. 

Relative      lymphocytosis 
and  decrease  of  polynuclear 
neutrophiles  common. 

Eosinophiles  notably  de- 
creased ;  often  absent. 

Myelocytes  very  rare. 

Basophiles  not  increased. 

a; 

(U 
!-i 
CJ 

Cl 
1— ( 

8 

■1 

1 

Erythrocytes. 

1 

i 

5 

244  DISEASES    OF    THE    BLOOD. 

VI.    LEUKEMIA. 
According  to  the  classification  in  general  vogue 

Varietix-.  ^^  ^i^g  present  time,  two  clinical  varieties  of  leu- 
iv^...-  ^.^^  splcno-medtdlary  and  the  lymphatic,  are 
recognized.  The  spleno-..^^^ll2^jy  variety,  which  is  almost  in- 
variably a  chronic  process,  is  «  ^^iated  with  a  marked  prolifera- 
tion of  myeloid  tissue,  and  is  charactei:--.f^  j^y  ^  striking  xv^-- ^i^viWa, 
and  generally  by  conspicuous  enlargement  oi  ...  v  Qt-'^cn  with  little 
or  no  involvement  of  the  lymphatic  glands.  The  lymphatic  form, 
which  may  run  either  an  acute  or  a  chronic  course,  more  com- 
monly the  latter,  is  a  process  associated  with  a  proliferation  of 
lymphoid  tissue,  and  is  characterized  by  a  blood-picture  known 
as  lymphemia  and  in  the  great  majority  of  cases  by  marked  en- 
largement of  the  lymphatic  glands  with  moderate  involvement  of 
the  spleen.  But  these  two  clinical  pictures,  in  so  far  as  they  relate 
to  the  splenic  and  lymphatic  hypertrophy,  are  by  no  means  con- 
stant, for,  although  cases  of  the  spleno-medullar}'  leukemia  always 
have  enlarged  spleens,  exceptionally  they  may  also  have  decided 
lymphatic  hyperplasia.  Furthermore,  cases  of  lymphatic  leukemia 
are  occasionally  encountered  in  which  there  is  a  marked  splenic 
tumor  without  demonstrable  signs  of  lymphatic  enlargement. 
Because  of  such  atypical  examples,  the  gross  appearance  of  the 
spleen  and  lymphatics  must  be  regarded  as  a  sign  of  distinctly 
secondary  importance  to  the  blood-picture,  which  is  alone  the  tan- 
gible diagnostic  clue. 

Of  the  two  forms  of  the  disease,  the  spleno-medullary  is  much 
the  commoner.  In  the  series  of  20  cases  of  leukemia  which  the 
writer  has  had  the  opportunity  of  studying,  1 2  were  of  the  spleno- 
medullar}^,  and  8  of  the  lymphatic  form;  while  of  Cabot's  41 
cases, ^  28  were  spleno-medullary  and  13  lymphatic — a  proportion 
of  about  two  of  the  former  to  one  of  the  latter,  for  the  combined 
series  of  61  cases. 

In  the  present  state  of  our  knowledge,  it  is 
Parasitology,  not  possible  to  regard  leukemia  as  a  disease  of  in- 
fectious origin,  notwithstanding  the  suggestive- 
ness  of  the  symptoms  shown  by  many  of  those  cases  which  run 
an  acute  course.  Within  the  past  few  years  several  investigators, 
notably  Delbert,"  Kelsch  and  Vaillard,^  Pallowski,*  and  Lowit^ 
have  attempted   to    ascribe  to   various  micro-organisms  specific 

^  Loc.  cit. 

2  Bull,  et  mem.  Soc.  de  chir.,  Paris,  1895,  vol.  xxi.,  p.  788. 

3Annal.  de  I'lnstitut  Pasteur,  1890,  vol.  iv.,  p.  276. 

*  Deut.  med.  Woch.,  1892,  vol.  xviii.,  p.  641. 

5  "  Die  Leukamie  als  Protozoeninfektion,"  Wiesbaden,  1900. 


LEUKEMIA.  245 

etiological  relationship  with  the  condition,  but  none  of  these  at- 
tempts have  thus  far  been  convincing.     L6 wit's  researches,  how- 
ever, are  worthy  of  special  attention,  if  for  no  other  reason  than 
the  elaborate  and  painstaking  study  which  they  represent.     This 
author  believes  that  two  distinct  forms  of  parasites  may  be  dem- 
onstrated in   leukemia  :  the  Jiemanieba  leukemicE  mazna,  thousrht 
to  be  the  specific  cause  of  the  spleno- medullary  form  of  the  dis- 
ease, and  the  heviameba  leukemics  parva,  which  he  claims  is  the 
definite  infective  principle  of  the  lymphatic  form.     These  so-called 
''  specific  bodies,"  which  are  found  both  in  the  blood  of  the  pe- 
ripheral vessels   and  in   the    hematopoietic    organs,  have  either 
a  granular  or  an  ameboid  appearance,  and  bear  a  more  or  less 
close  resemblance  to  the  basophile  granules  of  the  leucocytes  ; 
navicular,   segmenting,  and  vacuolated  forms  are    also  said    to 
occur.     They  are  either  attached  to,  or  lie  within,  the  leucocytes, 
especially  the  small  lymphocytes,  and  more  rarely  the  other  varie- 
ties of  normal  leucocytes  and  the  myelocytes ;  in  an  occasional 
instance  they  are  said  to  be  found  lying  free  in  the  plasma.     Al- 
though it  is  claimed  that  a  leucocytic  infection  has  been  produced 
in  animals  by  the  injection  of  blood  presumably  containing  these 
micro-organisms,  all  attempts  to  cultivate  them  on  artificial  media 
have  proved  futile.     L6 wit's  amebae  are  demonstrable  only  in  heat- 
fixed   specimens,  stained  preferably  with  a  steaming  hot  solution 
of  Loffler's  methylene-blue,  after  which  they  are  washed,  differ- 
entiated with  a  0.3  percent,  solution  of  hydrochloric  acid-alcohol, 
again  washed,  and   mounted.     In   specimens  thus   treated  they 
stain  metachromatically,  and,  if  the  acid-alcohol  differentiation 
has   been   properly  effected,  are   the  only  elements   except  the 
basophile  leucocyte  granules  which  retain  the  color  of  the  dye. 
Tiirk,^  who  has  followed  out  Lowit's  technique  precisely,  in  in- 
vestigating this  author's  claims,  has  come  to  the  conclusion  that 
these   "  specific  bodies  "  are  in  no  sense  of  parasitic  nature,  but 
merely  artefacts  resulting  from  the  action  of  an  aqueous  solution 
of  a  basic   dye   upon  the  mast  cell  granules,  which  causes  the 
partial   solution  of  the  latter  elements  and  deforms  them.     Turk 
claims,  furthermore,  that  these  so-called  amebae  can  be  produced 
both  in  the  normal  blood  of  man  and  in  the  blood  of  rabbits. 

1  XVIII.  German  Con.  for  Internal  Med.,  Wiesbaden,  Apr.  18-21,  1900. 


246  DISEASES    OF    THE    BLOOD. 


SPLENO-MEDULLARY  LEUKEMIA. 

The  drop  as  it  flows  from  the  puncture  is,  in 
Appearance  most  instances,  of  a  bright  scarlet  color,  and 
OF  the  often  has  a  peculiar  and  misleading  appearance 
Fresh  Blood,  of  density.  After  brief  exposure  to  the  air,  it 
may  split  up  into  two  portions,  a  serous,  scarlet 
fluid,  in  which  are  suspended  many  minute,  whitish,  fat-like 
masses  ;  the  former  appears  to  consist  of  serum  and  erythro- 
cytes, and  the  latter  of  adhering  masses  of  leucocytes.  It  was 
probably  this  striking  appearance  of  the  leukemic  blood  drop 
that  led  Hughes  Bennett  erroneously  to  describe  the  condition 
as  a  "suppuration  of  the  blood"  before  he  proposed  the  more 
suitable  term  leucocythemia.  In  some  cases  the  drop  is  simply 
much  darker  than  normal,  but  it  is  difficult  to  believe  that  it  ever 
resembles  the  chocolate-brown  shade  mentioned  by  some  authors 
as  occurring  in  this  disease.  The  blood  usually  flows  ver}''  freely 
from  the  wound,  often  by  fine  jets  and  spurts,  especially  if  slight 
pressure  is  applied  above  the  site  of  the  puncture. 

Microscopically,  the  field  is  found  to  contain  an  enormous 
number  of  leucocytes,  the  proportion  of  these  cells  to  the  er}'- 
throcytes  being,  by  actual  count,  as  great  as  i  to  8  or  6,  or 
even  greater.  Many  different  varieties  of  leucoc\i:es  may  be  dis- 
tinguished in  the  fresh  specimen,  the  most  striking  being  the 
large,  mononuclear,  finely  granular  cells  of  round  or  ovoid  shape. 
These  are  the  myelocytes  which  are  present  in  enormous  num- 
bers in  this  form  of  leukemia,  of  which  they  form  a  characteristic 
blood-picture.  **  Fractured "  leucocytes,  usually  eosinophiles, 
with  a  cloud  of  escaped  granules  free  in  the  plasma  in  the  neigh- 
borhood of  the  disrupted  cell  bod\',  may  also  be  observed  in  vari- 
able numbers,  although  such  cells  are  more  numerous  in  the 
dried,  stained  film.     ( See  Figs.  39  and  40.) 

The  er^'throcytes  vary  in  number  and  in  appearance  according 
to  the  severity  of  the  coexisting  anemia;  in  some  instances  large 
numbers  of  poikilocytes,  megalocytes,  and  microcytes,  with 
marked  pallor  of  the  corpuscles  may  be  seen,  while  in  others 
the  changes  affecting  the  er}^throcytes  appear  to  be  but  tri- 
fling. 

In  fresh  films  which  have  been  allowed  to  dr}-  for  some  time 
Charcot-Leyden  cr}'stals  may  sometimes  be  detected.  They  ap- 
pear as  colorless,  refractive  crystals,  shaped  like  octahedrons, 
having  long,  pointed,  sharp  angles,  and  occurring  either  singly  or 
in  twos  or  threes,  superimposed  at  right  angles  or  as  collections 
of  radiating  crj^stalline  masses.     These  crj^stals  are  not  obsen^ed 


PLATE  IV. 


13^^448^ 


Spleno-Medullary  Leukemia. 

(  Triacid  Stain.) 

1.  Small  Lymphocyte. 

2.  Large  Lymphocyte. 

Contrast  this  cell  with  the  myelocytes,  lo,  it,  and  12,  noting  the  presence  of  neutro- 
phile  granules  in  the  latter,  and  their  absence  in  the  lymphocyte.  The  size  and 
nuclear  characteristics  of  all  these  cells  are  practically  the  same. 

3.  4.  Polynuclear  Neutrophiles. 

5.  Eosinophile. 

In  this  "dwarf"  eosinophile,  ruptured  during  the  preparation  of  the  specimen,  the 
granules  are  peculiarly  arranged  about  the  nucleus;  no  signs  of  protoplasm  are  dis- 
tinguishable. 

6.  Eosinophilic  Myelocyte. 

Note  the  irregularity  with  which  the  granules  are  stained. 

7.  8,  9,  10,  II,  12,  13,  14,  15.    Myelocytes.     {Neutrophilic.) 

These  cells  varv  greatlv  in  size  (compare  8  with  9),  but  they  all  have  similar  distinc- 
tive characteristics — a  large  opalescent  nucleus  containing  a  scanty  chromatin  net- 
work embedded  in  a  cell  body  crowded  with  delicate  neutrophile  granules,  precisely 
like  those  found  in  the  polynuclear  neutrophiles,  3  and  4.  The  nucleus  of  7  is  dis- 
tinctly indented  and  somewhat  denser  than  that  of  the  other  myelocytes.  This  cell 
probably  represents  a  developmental  phase  of  the  myelocyte  just  short  of  its  transi- 
tion into  a  typical  polynuclear  neutrophile, 
16.    Normoblast. 

The  erythrocytes  (stained  orange)  show  many  evidences  of  deformity,  an  occasional 
megalocyte,  many  microcytes,  and  a  few  poikilocytes  being  present.  Polychromato- 
philia  is  absent. 

(E.    F.   FABER,/<?r.) 


SPLENO -MEDULLARY  LEUKEMIA.  24/ 

in  the  freshly  drawn  blood,  being  demonstrable  only  in  films 
which  have  stood  exposed  to  the  air  for  at  least  twenty-four 
hours,  and  only  occasionally  even  under  this  circumstance. 

On  account  of  the  presence  in  the  blood  of  such  large  numbers 
of  leucocytes,  a  very  small  drop  should  be  used  for  making  the 
cover-glass  spreads  for  staining,  since  it  is  advisable  to  avoid 
overcrowding  the  field  with  these  cells.  No  difficulty  will  be  ex- 
perienced in  obtaining  thin,  evenly  distributed  spreads,  if  this  pre- 
caution is  observed,  especially  if  the  cover-glasses  are  slightly 
warmed  just  before  they  are  used. 

The  coagulation  time  of  the  blood  and  the  for- 
CoAGULATiON.  mation  of  the  fibrin  network  must  be  regarded  as 
variable.  In  some  cases,  especially  those  with 
great  loss  of  hemoglobin  and  erythrocytes,  both  processes  are  de- 
layed and  imperfect,  as  evidenced  by  the  formation  of  the  *'  rasp- 
berry-jelly" clots  referred  to  by  the  German  writers.  But  in 
other  cases  the  coagulation  time  is  unaltered,  and  the  fibrin  net- 
work is  perfectly  normal. 

The  alkalinity  of  the  blood  is  usually  decreased. 
Alkalinity,  and,  as  in  chlorosis,  it  increases  after  the  patient 
is  given  iron,  in  parallelism  with  the  gain  in  hem- 
oglobin and  erythrocytes.  In  3  cases  studied  by  Burmin,^  an 
average  alkalinity  equivalent  to  0.146  grm.  was  found,  Landois' 
method  being  employed  in  the  investigations.  Taylor^  found  an 
average  of  0.380  grm.  in  three  cases,  tested  by  the  von  Limbeck 
method. 

In  cases  with  severe  anemia  the  density  of  the 
Specific        blood  may  fall  as   low  as  1035  or  1040.     Gra- 
Gravity.       witz  ^  has  reported  a  case  in  which  the  figure  was 
1023.     The   fallacies   in  leukemia   of  Hammer- 
schlag's  tables  of  specific  gravities  and  their  hemoglobin  equiva- 
lents have  already  been  pointed  out.     (See  page  100.) 

Decided   hemoglobin  and  eiythrocyte  loss  is 

Hemoglobin    the  invariable  rule  sooner  or  later  during   the 

AND  course  of  the  disease,  the  anemia  usually  being 

Erythrocytes,  well  defined  at  the  time  the  patient  first  comes 

under  observation,  and  becoming  acutely  marked 

as  the  termination  of  the  illness  approaches.     It  is  generally  the 

case  that  the  hemoglobin  loss  is  disproportionately  greater  than 

the  decrease  in  the  erythrocytes,  thus  producing  a  moderately 

low  color  index,  but  in  some  cases  just  the  opposite  of  this  is  ob- 

^  Loc.  cit. 
2  Loc.  cit. 
"Loc.  cit. 


248  DISEASES    OF    THE    BLOOD. 

served.^  In  the  writer's  12  cases,  grouped  in  Table  VI.,  the 
color  index  averaged  about  0.9,  being  i.oo  or  higher  in  one-third 
of  the  cases,  and  not  falling  below  0.50  in  the  remaining  two-thirds, 
being  usually  above  0.65.  The  hemoglobin  percentage  ranged 
between  30  and  70,  averaging  49  ;  and  the  number  of  erythro- 
cytes was  as  low  as  2,000,000  and  as  high  as  4,000,000  per  cubic 
millimeter,  the  mean  average  being  about  2,800,000  ;  the  count 
of  these  cells  was  diminished  to  one-half  of  the  normal  standard, 
or  below  this  figure,  in  exactly  one-half  of  the  cases  examined. 
An  analysis  of  Cabot's  series  of  28  cases  of  spleno-medullary 
leukemia^  shows  these  average  findings,  which  are  not  mate- 
rially different  from  those  just  given  :  hemoglobin,  52  per  cent.; 
erj^throcytes,  3,120,000  per  cubic  millimeter;  and  color  index, 
about  0.6. 

Fluctuations  in  the  hemoglobin  percentage  and  the  number  of 
er>^throcytes  may  or  may  not  accompany  variations  in  the  leuco- 
cyte count.  Sometimes,  as  the  leucocytes  rise,  the  erj^throcytes 
fall,  but  again  they  remain  practically  stationary ;  or,  the  leuco- 
cytes may  progressively  fall  to  a  comparatively  moderate  count, 
coincidentally  with  an  apparent  improvement  in  the  patient's  gen- 
eral condition,  and  yet  the  erythrocytes  do  not  materially  gain  in 
numbers.  Taylor  ^  refers  to  two  such  instances  which  have  come 
under  his  observation,  in  both  of  which  the  blood-picture  at  cer- 
tain brief  intervals  resembled  that  of  pernicious  anemia,  for  under 
the  influence  of  energetic  arsenical  treatment  the  leucocytes  were 
reduced  to  normal,  while  the  oligocythemia  stubbornly  persisted. 
In  a  case  studied  for  a  protracted  period,  it  is  possible  to  distin- 
guish a  general  decrease  in  the  erythrocyte  count  as  the  leuco- 
cytes increase,  although  the  reverse  may  not  be  true.  (See  Chart 
II.,  page  250.) 

Examination  of  the  stained  specimen  shows  the  presence  of 
nucleated  erythrocytes  in  practically  every  case  of  spleno-medul- 
lary leukemia,  these  cells  often  being  many  times  more  numerous 
than  in  grave  cases  of  pernicious  anemia.  Normoblasts  prevail, 
always  being  more  numerous  than  megaloblasts  ;  in  some  cases 
they  are  the  only  type  of  erj^throblast  to  be  observed ;  in  others 
they  are  associated  with  a  relatively  moderate  number  of  typical 

^  It  is  to  be  remembered  that  hemoglobin  estimates  in  leukemia  may  be  unreliable 
(except  when  Dare's  instrument  is  used),  for  correct  readings  are  sometimes  impos- 
sible, owing  to  the  milkiness  of  the  diluted  blood  from  the  presence  of  such  immense 
numbers  of  leucocytes.  Three-fourths  of  the  hemoglobin  figures  in  the  accompany- 
ing table  (Table  VI.)  were  obtained  by  means  of  von  Fleischl's  hemometer,  the 
remainder  being  based  upon  examinations  with  Oliver's  instrument. 

2  Loc.  cit. 

3  Log.  cit. 


SPLENO -MEDULLARY    LEUKEMIA. 


Table  VI . 


249 


Hemoglobin  and  Erythrocytes    in   Spleno-Medullary  Leukemia,  at  the 
First  Examination.     12  Cases, 


Number. 

Hemoglobin  Percen- 

 » 

Color  Index. 

Erythrocytes  per 

tage. 

cb.  mm. 

I 

70 

.87 

4,000,000 

2 

45 

.51 

3,973,000 

3 

68 

.90 

3,760,000 

4 

45 

.66 

3,400,000 

5 

40 

.65 

3,100,000 

6 

70 

1.37 

2,550,000 

7 

60 

1.30 

2,300,000 

8 

33 

.71 

2,300,000 

9 

40 

.87 

2,287,000 

10 

45 

1. 12 

2,160,000 

II 

40 

1. 00 

2,000,000 

12 

30 

•75 

2,000,000 

Average  : 

49 

.89 

2,819,167 

megaloblasts,  or,  more  commonly,  with  large  numbers  of  atypical 
forms,  sharing  the  characteristics  of  the  typical  adult  and  em- 
bryonic nucleated  erythrocytes.  In  the  9  cases  of  this  variety  of 
leukemia  in  which  the  writer  has  made  differential  erythrocyte 
counts,  the  following  estimates  were  obtained,  at  the  first  exami- 
nations : 


Number. 

Total    number  of   ery- 

Normoblasts  per 

Megaloblasts  per 

throblasts  per  cb.  mm. 

cb.  mm. 

cb.  mm. 

I 

12,913 

8,376 

4,537 

2 

9,178 

9,178 

0 

3 

8,626 

7,264 

1,362 

4 

8,064 

6,048 

2,016 

5 

5,694 

3,504 

2,190 

6 

3.234 

1,848 

1,386 

6 

2,940 

2,940 

0 

8 

1,980 

1,980 

0 

9 

748 

748 

0 

Average  : 

5,931 

4,654 

1,277 

Comparison  of  the  above  summary  with  the  table  giving  the 
number  and  forms  of  erythroblasts  in  pernicious  anemia  (Table 
IV.,  page  224)  illustrates  two  striking  facts  concerning  these 
cells  in  spleno-medullary  leukemia  :  the  immense  numbers  in 
which  they  occur,  and  the  predominance  of  normoblasts  over 
megaloblasts.  Periods  of  temporary  improvement  in  the  pa- 
tient's general  health  are  often  heralded  by  a  notable  increase  in 
the  normoblasts,  but  it  is  a  noteworthy  fact  that  during  these  re- 


250  DISEASES    OF    THE    BLOOD. 

missions,  while  the  leucocytes  may  fall  decidedly,  the  normo- 
blasts tend  to  persist  in  greater  or  less  numbers. 

Examples  of  so-called  nuclear  extrusion,  of  multinucleation, 
of  clover-leaf,  dumb-bell  or  other  irregularly  formed  nuclei,  and 
even,  in  rare  instances,  of  karyokinesis  are  observed  in  many  of  the 
normoblasts.  Such  alterations  may  be  more  conspicuous  in 
highly  developed  cases  of  spleno-meduUary  leukemia  than  in  any 
other  disease  of  the  blood.  In  an  occasional  normoblast  the 
contracted,  glistening,  intensely  basic  nucleus  is  highly  sugges- 
tive of  pyknosis.  No  one  who  has  done  much  blood  work  can 
fail  to  be  struck  with  the  obvious  avidity  displayed  by  the  stroma 
of  the  erythroblasts  for  the  acid  fuchsin  of  the  triple  stain — a 
peculiarity  which  is  exhibited  in  spite  of  good  technique  and  the 
use  of  a  reliable  staining  solution. 

Deformities  affecting  the  size  and  the  shape  of  the  erythrocytes 
may  be  trivial  or  decided,  depending  upon  the  degree  of  hemo- 
globin and  erythrocyte  loss  present.  PolycJiroinatopJiilia,  alone, 
or  associated  with  basophilic  stroma  dege?ieratio7i,  is  w^ry  com- 
mon in  cases  with  great  anemia,  the  former  especially  affecting 
the  nucleated  eiythrocytes,  and  the  latter  the  non-nucleated  cells. 
Striking  increase  in  the  number  of  leucocytes 
Leucocytes,  is  found  even  during  the  early  stages  of  the  dis- 
ease. Counts  of  from  200,000  to  300,000  cells 
to  the  cubic  millimeter  are  common  ;  counts  of  from  300,000 
to  500,000  are  less  frequently  observed ;  but  only  occasionally 
does  the  estimate  exceed  the  latter  figure.  In  rare  instances  the 
number  of  leucocytes  may  be  as  high  as  1,000,000  per  cubic 
millimeter.  It  has  been  stated  by  competent  authorities  that  the 
leucocyte  count  may  equal  or  even  exceed  that  of  the  erj^thro- 
cytes,  and  it  is  easy  to  see  that  such  a  condition  is  possible, 
should  the  accompanying  oligocythemia  be  intense.  In  the  esti- 
mates given  in  Table  VII.,  showing  the  number  of  leucocytes  at 
the  time  the  patient  first  applied  for  treatment,  the  average  count 
was  281,623  P^^  cubic  millimeter,  the  highest  being  544,000,  and 
the  lowest  44,000.  The  greatest  number  of  leucocytes  found  in 
these  cases  at  any  time  was  706,000,  this  estimate  having  been 
made  a  few  hours  before  the  patient's  death. 

The  number  of  leucocytes  may  fluctuate  enormously  at  various 
times  during  the  progress  of  the  disease,  a  gain  or  a  loss  of  some 
200,000  cells  to  the  cubic  miUimeter  from  week  to  week  being  a 
matter  of  common  occurrence.  Sometimes  they  are  temporarily 
diminished  as  the  result  of  the  administration  of  arsenic  to  the 
point  of  tolerance,  or  of  the  vigorous  employment  of  other  ther- 
apeutical  measures  ;    sometimes  the  decrease  takes  place  inde- 


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SPLENO-MEDULLARY  LEUKEMIA. 
Red,  Hemoglobin.  Black,  Erythrocytes.  Blue,  Leucocytes. 


SPLENO -MEDULLARY    LEUKEMIA. 


251 


Table  VII. 
Number  of  Leucocytes  and  Percentage  of  Various  forms  in  Spleno- 

MEDULLARY    LEUKEMIA,    AT   THE    FlRST    EXAMINATION.       12    CaSES. 


Leucocytes  per 
cb.  mm. 

Percentage  of  Diflferent  Forms. 

No. 

Small  lymph- 
ocytes. 

Large  lymph- 
ocytes. 

Polynuclear 
Neutrophiles. 

54-7 

Eosino- 
philes. 

Myelo- 
cytes. 

Baso- 
philes. 

I 

544,000 

1-3 

5.6 

5-6 

30.8 

2 

2 

450,000 

I.O 

2.2 

60.0 

28.7 

7-1 

I 

3 

446,420 

II. 0 

2.5 

60.5 

6.5 

19-5 

- 

4 

370,000 

1,0 

9.0 

51.0 

5-0 

34.0 

- 

■> 

358,000 

2.0 

150 

63.0 

4.0 

16.0 

- 

6 

285,000 

2.5 

lO.O 

65-5 

4-5 

17-5 

- 

7 

245,000 

8.0 

8.0 

54-5 

9.0 

20.5 

— 

8 

222,300 

7.0 

15.0 

63.0 

4.0 

II. 0 

- 

9 

168,750 

1.0 

6.0 

51.0 

12.0 

30.0 

- 

10 

144,000 

12.0 

18.0 

45-0 

4.0 

21.0 

- 

II 

102,000 

0.7 

03 

73-6 

2.1 

23-3 

- 

12 

44,000 

6.8 

5-6 

70.8 

2.0 

14.8 

- 

Av. 

281,623 

4-5 

8.1 

59-4 

7-3 

20.5 

•25 

pendently  of  the  influence  of  remedial  agencies,  so  far  as  can  be 
determined.  When  arsenic  is  withheld  the  number  of  leucocytes 
promptly  increases,  and  in  spite  of  its  use  they  ultimately  increase, 
as  the  disease  runs  its  fatal  course.  The  relations  of  the  leuco- 
cytes' fluctuations  to  the  number  of  erythrocytes  have  already 
been  mentioned.  Hayek  ^  has  drawn  attention  to  the  fact  that  in 
the  leukemic  individual  the  morning  leucocyte  count  may  be 
greater  by  more  than  100,000  cells  per  cubic  millimeter  than  the 
estimate  made  during  the  afternoon,  and  vice  versa.  In  a  case  in 
Professor  Wilson's  wards  at  the  Jefferson  Hospital,  the  writer 
has  been  able  to  verify  this  statement,  the  counts  being  as  fol- 
lows :  1 1  a.  m.,  144,000  ;  6  p.  m.,  256,000 — a  difference  of  1 12,- 
000  cells  within  a  period  of  seven  hours.  The  influences  of  di- 
gestion and  other  sources  of  error  were,  of  course,  excluded  in 
making  this  observation.  The  occurrence  of  this  enormous 
diurnal  fluctuation  emphasizes  the  importance  of  making  the 
blood  examination  of  leukemic  patients  at  precisely  the  same  hour 
each  day,  in  cases  studied  for  a  long  period. 

The  possibility  of  encountering  a  case  of  leukemia  during  a 
period  of  remission,  when  the  typical  blood  changes  are  absent, 
must  be  borne  in  mind,  for  such  instances  are  observed  from  time 
to  time,  although  they  are  very  rare.  For  example,  McCrae^ 
reports  a  case,  treated  by  arsenic,  in  which  twice  during  a  period 

^Wien.  klin.  Woch.,  1897,  vol.  x.,  p.  475. 
2  Brit.  Med.  Journ.,  1900,  voL  i.,  p.  760. 


252  DISEASES    OF    THE    BLOOD. 

of  ten  months  the  blood  and  general  symptoms  of  the  patient 
were  typical  of  spleno-medullary  leukemia,  and  twice  were  abso- 
lutely normal.  When  first  examined,  this  patient's  leucocytes 
numbered  584,000  per  cubic  millimeter,  three  months  later  they 
had  fallen  to  9,250,  two  months  after  this  they  had  risen  to  178,- 
000,  and  after  a  lapse  of  another  five  months  they  again  fell  to 
5,000.  These  fluctuations  did  not  depend  upon  the  influence  of 
any  intercurrent  infection  (see  below),  and  the  case  is  unique  in 
that  the  leucocytes  (as  well  as  the  erythrocytes)  not  only  were 
normal  in  number,  but  also  normal  qualitatively,  and  in  that  the 
patient's  splenic  tumor  entirely  disappeared  during  the  periods 
of  remission.  Other  cases  have  been  recorded  showing  brief 
periods  of  temporar}^  decline  to  normal  in  the  number  of  leuco- 
cytes, but  with  the  persistence  of  myelocytes,  or  of  the  splenic 
enlargement,  or  of  both. 

The  presence  of  myelocytes  in  large  numbers  is  the  hinge  upon 
which  the  diagnosis  of  spleno-medullary  leukemia  must  turn,  for 
in  no  other  disease  are  these  cells  so  numerous,  or  so  constantly 
present.  A  high  percentage  of  myelocytes,  irrespective  of  the 
degree  of  increase  in  the  total  number  of  leucocytes  of  all  forms, 
is  as  essential  for  the  diagnosis  of  this  variety  of  leukemia  as  is  a 
predominance  of  megaloblasts  for  the  recognition  of  pernicious 
anemia.  In  most  cases  they  constitute  at  least  20  per  cent,  of 
the  different  forms  of  leucocytes,  and  occasionally  as  high  as  50 
per  cent,  or  more.  In  the  1 2  cases  of  the  present  series  (Table 
VII.)  the  myelocytes,  at  the  first  counts,  averaged  20.5  per  cent., 
with  7.1  and  34.0  per  cent,  as  the  minimum  and  maximum  esti- 
mates, respectively.  It  is  the  fact,  not  that  myelocytes  simply 
occur  in  this  disease,  but  that  they  occur  in  such  enormous 
numbers,  that  is  of  prime  value  in  the  diagnosis,  since  in  no  other 
condition  in  which  this  type  of  marrow  leucocyte  is  found  in  the 
blood,  are  they  present  in  such  striking  abundance.  For  example, 
although  myelocytes  are  very  constant  in  pernicious  anemia,  they 
are  only  about  one-twentieth  as  numerous  in  this  disease,  on  the 
average,  as  they  are  in  spleno-medullary  leukemia. 

Many  of  the  myelocytes  are  of  very  large  size,  some  being 
quite  22  fi  in  diameter  and  occasionally  of  somewhat  larger  di- 
mensions ;  others  are  dwarfed  to  no  larger  than  the  diameter  of 
a  small  lymphocyte.  The  nuclei  of  these  larger  forms  usually 
stain  with  relatively  less  intensity  than  those  of  the  smaller. 
Indentation,  apparent  division,  and  hour-glass  constriction  of  the 
myelocytes'  nuclei  are  also  frequently  noted.  A  very  common 
form  of  this  cell  in  spleno-medullary  leukemia  is  characterized  by 
its  large  size  and  its  jfele,  kidney-shaped  nucleus,  the  regularly 


SPLENO-MEDULLARY    LEUKEMIA.  253 

convex  border  of  which  Hes  in  intimate  contact  with  fully  one- 
half  the  peripheiy  of  the  cell  body.  These  and  other  atypical 
forms  of  myelocytes   are   shown  in  the  accompanying  illustra- 


FiG.  39. 


^^^    .       .      Jim-'. 


-,y?-. 


12  3  456 

Atypical  forms  of  myelocytes  in  spleno-medullary  leukemia. 

(Ehrlich's  triacid  stain.) 
I,  2.  Dwarf  forms,  with  relatively  large  and  deeply  stained  nuclei  situated  in  a  relatively  small 
amount  of  cell  body  containing  neutrophile  granules.     3.  "  Fractured  "  myelocyte.     4.  Extremely 
large  form,  with  kidney-shaped  nucleus.    5.  Eosinophilic  myelocyte  with  deeply  constricted  nucleus. 
6.  Myelocyte  having  an  hour-glass  :;onstriction  of  the  nucleus. 

tion.  The  abnormalities  affecting  the  granules  of  this  type 
of  cells,  as  well  as  certain  degenerative  changes,  do  not  differ 
from  those  which  are  found  in  the  polynuclear  neutrophils  de- 
scribed below. 

The  relative  percentage  of  polynuclear  netitrophiles  is  low,  but 
not  especially  so,  although  of  course  the  absolute  number  of 
this  type  of  cells  is  greatly  in  excess  of  the  normal  standard,  as 
may  be  demonstrated  by  taking  into  consideration  the  high  total 
leucocyte  count.  For  instance,  in  a  case  having  300,000  leuco- 
cytes per  cubic  millimeter,  with,  say,  50  per  cent,  of  them  poly- 
nuclear neutrophiles,  the  actual  number  of  the  latter  is  1 50,000 
to  the  cubic  millimeter,  or  fifteen  times  the  maximum  normal 
number.  The  cases  listed  in  Table  VII.  averaged  59.4  per 
cent,  for  this  variety  of  leucocytes,  with  a  range  between  45.0 
and  73.6  per  cent,  in  the  individual  case,  but  other  authors, 
with  more  extended  series  of  cases  as  a  basis  for  their  statistics, 
give  lower  figures  than  these. 

A  feature  which  at  once  attracts  attention  in  the  examination 
of  the  stained  specimen  is  the  deviation  from  the  normal  size  of 
a  large  proportion  of  these  neutrophilic  cells.  Dwarfed  cells, 
often  not  more  than  5  or  6  //  in  diameter,  and  large  forms,  some 
of  them  measuring  1 5  ^w  or  even  more  in  diameter,  are  common, 
the  nuclei  of  the  former  usually  staining  much  more  sharply  than 
those  of  the  latter,  which  may  exhibit  a  very  feeble  reaction  to- 
ward the  basic  dye,  and  show  a  more  diffuse  and  delicate  chro- 
matin  structure  than  is  the  rule  in   norrrial  blood.     The  nuclei 


2  54  DISEASES    OF    THE    BLOOD. 

also  tend  to  exhibit  extreme  polymorphism  and  variations  in  their 
relative  size  to  that  of  the  cell  body.  Many  of  these  cells  are 
also  deformed  in  shape,  being  drawn  out  into  various  oblong 
and  elliptical  designs  or  into  irregular  elongated  masses.  '*  Frac- 
tured "  cells,  from  which  the  granules  hav^e  escaped,  are  also 
commonly  seen.  It  seems  reasonable  to  attribute  the  free  neu- 
trophil granules  sometimes  seen  in  the  blood  in  this  disease  to 
the  rupture  of  a  neutrophilic  leucocyte,  although  the  particular 
cell  to  which  they  belonged  may  be  difficult  to  identify  ;  the  view 
expressed  by  some  authors  that  such  granules  may  preexist  in 
the  plasma  is  scarcely  to  be  thought  of  seriously.  All  of  these 
deformities  are  doubtless  the  result  of  injuries  to  the  cells  in  the 
preparation  of  the  cover-glass  spreads,  and  they  suggest  a  lowered 
resistance  on  the  part  of  the  leucocytes. 

The  number  of  granules  in  the  polynuclear  neutrophiles  varies 
greatly  in  the  individual  cells  ;  in  some  they  are  densely  crowded 
throughout  the  protoplasm  and  overrun  portions  of  the  nucleus  ; 
in  others  they  are  confined  to  certain  areas  of  the  cell  body,  es- 
pecially in  the  neighborhood  of  the  nucleus  ;  w^hile  in  still  others 
they  are  distributed  singly  or  in  twos  and  threes  through  the 
protoplasm.  Occasionally  a  cell  wholly  devoid  of  granules  is 
observed,  and,  very  rarely,  one  containing  both  neutrophile  and 
a  few  isolated  eosinophile  or  basophile  granules.  The  neutro- 
phile granules  themselves  vary  greatly  in  size,  being  in  some 
cells  so  extremely  delicate  and  fine  that  they  can  be  barely  dis- 
tinguished, while  in  others  they  almost  equal  the  size  of  the 
smaller  eosinophile  granules. 

Fig.  40. 


"^    '  I  l-*' 


I  2  3 

Atypical  forms  of  polynuclear  neutrophiles  in  spleno-medullary  leukemia. 

I.  Cell  containing  both  neutrophile  and  moderately  coarse  basophile  granules.  2.  Polynuclear 
cell,  with  two  ovoid  nuclei  and  neutrophile  granules,  probably  representing  a  later  developmental 
stage  than  6,  Fig.  39.  3.  "  Fractured  "  polynuclear  neutrophile.  (No.  i  stained  with  Jenner's  eosin- 
ate  of  methylene-blue,  2  and  3  with  Ehrlich's  triacid  stain.) 

Fine  and  coarse  vacuolation  of  the  nucleus  and  protoplasm,  a 
fissured  and  cracked  appearance  of  the  nuclear  chromatin,  and  an 
apparent  solution  of  the  protoplasm  with  freeing  of  the  nu- 
cleus are  the  most  prominent  degenerative  changes  affecting  the 


SPLENO -MEDULLARY  LEUKEMIA.  255 

polynuclear  neutrophiles,  as  well  as  the  other  varieties  of  leuco- 
cytes, in  this  disease. 

The  relative  percentage  of  lymphocytes,  small  and  large  to- 
gether, is  decidedly  lower  than  normal,  although  their  total  num- 
ber to  the  cubic  millimeter  of  blood  is  greatly  increased.  As 
shown  by  the  cases  in  Table  VII.,  these  cells  average  a  trifle 
more  than  12  per  cent,  of  all  varieties  of  leucocytes,  which  rep- 
resents a  diminution  to  about  one-third  of  the  proportion  found 
in  normal  blood.  It  is  the  small  lymphocytes  which  suffer  the 
greater  loss,  for  their  proportion  in  the  differential  count  is  some- 
times not  more  than  a  fraction  of  i  per  cent.,  and  always  greatly 
below  normal;  the  large  lymphocytes  and  **  transitional  "  forms, 
on  the  contrary,  average  about  normal,  and,  indeed,  may  be 
increased  in  the  individual  case.  Turk's  ^'  stimulation  forms''  are 
also  met  with,  but  these  cells  as  a  rule  are  not  numerous. 

Atypical  forms  of  lymphocytes  are  not  so  common  in  this  form 
of  leukemia  as  they  are  in  the  lymphatic  variety.  Such  cells  are 
described  under  the  latter  disease.     (See  page  259.) 

Eosinophilia,  as  indicated  by  an  increase  in  the  total  number  of 
eosinophils,  is  invariably  found,  and  an  increase  above  normal  in 
the  relative  percentage  of  these  cells  sometimes,  but  not  always, 
exists.  Thus,  in  the  above-mentioned  series  the  eosinophiles, 
which  normally  do  not  exceed  500  per  cubic  millimeter,  ranged 
from  880  to  129,150  and  averaged  20,558  per  cubic  millimeter, 
these  figures  corresponding  to  percentages  of  2.0,  28.7,  and  7.3, 
respectively. 

Ehrlich's  original  statement  regarding  an  increase  of  the  eosino- 
philes in  this  form  of  leukemia  has  been  contradicted  by  several 
writers,  notably  by  von  Limbeck,^  and  by  Miiller  and  Rieder^; 
but  these  contradictions  are  based  upon  a  misconception  of  Ehr- 
lich's remarks,  for  the  latter  never  claimed  that  an  abnormally 
high  percentage  of  eosinophiles  was  associated  with  this  disease, 
but  said  simply  that  their  absolute  number  was  increased. 

Marked  variation  in  the  size  of  many  of  the  eosinophiles  is  com- 
monly observed,  dwarf  forms,  5  or  6  /i  in  diameter,  with  densely, 
crowded  and  deeply  stained  granules,  being  especially  striking 
and  apparently  more  numerous  than  the  larger  forms.  Eosino- 
philic myelocytes,  differing  from  ordinaiy  neutrophilic  myelocytes 
only  in  that  they  are  studded  with  eosinophile  granules,  are  very 
numerous,  and  are  among  the  largest  forms  of  the  myelocyte 
found  in  this  disease.  "  Fractured  "  eosinophiles  are  common, 
being  usually  more  abundant  than  neutrophilic  cells  which  have 

^  Loc.   cit. 

2Deut.  Archiv.  f.  klin.  Med.,  1891,  vol.  xlviii.,  p.  96. 


256  DISEASES    OF    THE    BLOOD. 

thus  traumatically  suffered.  In  some  of  the  eosinophiles  the 
granules  are  scanty,  and  in  many  their  size  varies  greatly.  Un- 
usually large-sized  granules  are  often  found,  especially  in  the 
dwarf  cells  and  in  the  extremely  large  forms. 

Basopliilcs,  both  the  forms  overcrowded  with  delicate,  pure 
basic  granules,  and  mast  cells  with  relatively  fewer,  coarse,  meta- 
chromatic granules,  are  found  with  great  constancy,  being  absent 
in  but  a  small  proportion  of  cases.  The  latter  type  of  cell  is  es- 
pecially suggestive  of  leukemia  of  this  variety,  since  in  no  other 
disease  does  it  occur  in  such  large  numbers.  In  some  leukemic 
bloods  the  mast  cells  attain  an  enormous  size,  being  quite  the  larg- 
est cellular  elements  found  in  the  specimen.  They  may  be 
easily  identified  by  their  characteristic  reaction  toward  the  basic 
dyes,  described  in  a  previous  section.      (See  page  170.) 

From  the  above  remarks,  it  may  be  concluded  that  myelocytes 
are  present  in  the  circulating  blood  at  the  expense  of  all  the 
normal  varieties  of  leucocytes  except  the  eosinophiles,  and  that 
the  brunt  of  this  decrease  is  sustained  by  the  mononuclear,  non- 
granular forms,  chiefly  by  the  small  lymphocytes. 

These  bodies  are  greatly  increased  in  number 

Blood         in  most  cases  of  this  form  of  leukemia,  and  may 

Plaques.        frequently  be  recognized  in   the  fresh  specimen 

and  in  the  diluted  blood  in  the  counting  chamber 

of  the  hemocytometer.     They  are  seldom  observed,  however,  in 

the  stained  film  prepared  by  ordinar)^  methods. 

LYMPHATIC    LEUKEMIA. 

In  most  cases  the  blood  drop  is  watery-looking, 

Appearance    pale,  and  thin,  for  in  this  variety  of  leukemia  the 

OF  THE         anemia  is  usually  very  marked.     The  milky  ap- 

Fresh  Blood,  pearance  of  the  drop,  frequently  observed  in  the 

spleno-medullary  form  of  the  disease,  is  not  often 

noticed  in  the  lymphatic  variety. 

The  alterations  in  the  coagulability,  alkalinity,  and  specific 
gravity  of  the  whole  blood  are  similar  to  those  met  with  in 
spleno-medullary  leukemia. 

Microscopically,  the  field  is  crowded  with  large  numbers  of  leu- 
cocytes, the  vast  majority  of  which  are  mononuclear  cells  encir- 
cled by  a  perfectly  hyaline,  non-granular  protoplasm.  They  may 
be  quite  uniformly  of  either  small  or  large  size,  or  so  many  inter- 
mediate sizes  may  be  present  that  it  is  impossible  to  distinguish 
any  single  predominating  type.  It  is  apparent  that  the  leuco- 
cytes do  not  seem  so  numerous  as  in  spleno-meduUar}^  leukemia, 
nor  are  their  characteristics  so  striking,  at  first  glance,  because  of 


PLATE  V. 


12 


4       ^ 


11 


"■^^^ 


Lymphatic  Leukemia. 
{ Triacid  Stain.) 


i>  2,  3.  4.  5.  6.   Small  Lymphocytes. 

These  cells  show  a  great  difference  in  the  intensity  of  their  reaction  toward  the  basic 
dye.  The  smallest  forms,  1,2,4,  and  5,  being  richer  in  nuclear  chromatin  and  staining 
more  deeply  than  the  larger,  3  and  6.     Compare  2  with  the  normoblast,  16,  Plate  IV. 

7,  8,  9,  10,  II.   Large  Lymphocytes, 

Except  in  10,  which  shows  a  delicate  rim  of  fuchsin-stained  protoplasm,  these  Ivmpho- 
cytes  appear  simply  as  pale  chromatin-deficient  nuclear  structures,  lacking  cell  bodies 
Compare  these  cells  with  the  myelocytes,  Plate  IV. 

12.    Transitional  Form. 

The  upper  edge  of  the  nucleus  is  somewhat  indented  and  the  protoplasm  is  distin- 
guishable; otherwise  this  cell  resembles  a  large  lymphocyte. 

(E.  F.  Faber,  y^c.) 


LYMPHATIC  LEUKEMIA. 


257 


the  entire  lack  of  granulations  in  their  protoplasm.  The  differ- 
ence between  these  hyaline  cells  and  the  granular  leucocytes  of 
the  last-named  disease,  even  although  they  may  not  happen  to 
differ  greatly  in  size  and  shape,  is  at  once  patent  to  the  practised 
eye.  The  changes  affecting  the  size,  color,  and  shape  of  the  eryth- 
rocytes vaiy  with  the  degree  of  oligochromemia  and  oligocy- 
themia present ;  they  are  generally  quite  decided,  as  in  any  high- 
grade  anemia. 

Marked  anemia,  characterized  by  a  dispropor- 
Hemoglobin    tionate  diminution  in  hemoglobin,  is  the  general 
AND  rule  in  this  variety  of  leukemia,  the  decrease  in 

Erythrocytes,  both  hemoglobin  and  erythrocytes,  especially  in 
the  former,   being    usually  greater  than  in  the 
spleno-medullary  form.      Compared  with  the   latter,  the  hemoglo- 
bin loss  averages  about  twice  as  much,  the  erythrocyte  decrease 
is  more  than  10  per  cent,  greater,  and  the  color  index  is  just  30. 

Table  VIII. 

Hemoglobin  and  Erythrocytes  in  Lymphatic  Leukemia,  at  the  First  Ex- 
amination.    8  Cases. 


Number. 

Hemoglobin 

Color  Index. 

Erythrocytes  per 

Percentage. 

cb.  mm. 

I 

29 

.40 

3,590,000 

2 

40 

.66 

3,000,000 

3 

31 

.58 

2,690,000 

4 

20 

.43 

2,310,000 

5 

23 

.50 

2,266,000 

6 

18 

.50 

1,800,000 

7 

14 

•55 

1,270,000 

8 

25 

1.09 

1,152,000 

Average  : 

25 

0.59 

2,259,750 

points  lower.  In  the  Hmited  number  of  cases  listed  in  Table  VIII. 
the  following  estimates  were  obtained  at  the  first  examinations  : 
average  hemoglobin  percentage,  25,  ranging  from  14  to  40  per 
cent.  ;  average  erythrocyte  count,  2,259,750,  or  from  1,152,000 
to  3,590,000  per  cubic  miUimeter  ;  and  average  color  index,  0.59, 
with  a  minimum  of  0.40  and  a  maximum  of  1.09.  In  rare  in- 
stances the  number  of  erythrocytes  falls  below  1,000,000,  and  the 
hemoglobin  so  low  that  it  is  impossible  to  estimate  the  percentage 
at  all  accurately.  Rapidly  developing  and  extremely  pronounced 
anemia  is  generally  observed  in  cases  which  pursue  an  acute  course. 
Nucleated  erythrocytes^  chiefly  of  the  normoblastic  type,  are 
commonly  found  in  moderate  numbers,  but  never,  except  in  rare 
instances  usually  occurring  in  children,  are  they  as  numerous  as 
17 


258 


DISEASES    OF    THE    BLOOD. 


in  the  spleno-medullary  form  of  the  disease.  As  a  rule,  when 
both  normoblasts  and  megaloblasts  are  present,  the  former  vastly 
outnumber  the  latter,  although  occasionally  one  meets  with  a 
case  in  which  this  predominance  of  adult-type  er>^th  rob  lasts  is 
less  pronounced.  Thus,  in  one  of  the  writer's  cases  the  total 
number  of  erj'throblasts  was  calculated  at  10,678  per  cubic  mil- 
limeter, of  which  8,512  were  normoblasts  and  2,166  megalo- 
blasts ;  such  a  blood-picture  as  this,  however,  is  but  seldom 
found.  In  general  terms,  it  may  be  said  that  the  more  acute  the 
form  of  the  disease,  the  more  decided  the  oligochromemia  and 
oligocythemia,  and  the  more  abundant  the  erythroblasts,  the 
number  and  character  of  which  appear  to  depend  upon  the  grade 
of  the  anemia  present.  It  should  not  be  forgotten  that  in  some 
cases  of  typical  lymphatic  leukemia  nucleated  erythrocytes  are 
so  scanty  that  they  are  detected  only  after  repeated  examinations. 
Deformities  of  size  and  shape,  and  atypical  staining  of  the  eryth- 
rocytes are  marked  in  direct  relation  to  the  severity  of  the  anemia. 
The  number  of  leucocytes  is  largely  increased. 
Leucocytes,  but  usually  much  less  strikingly  so  than  in 
spleno-medullary  leukemia,  in  which,  generally 
speaking,  their  number  averages  about  three  times  greater.  In 
the  latter  it  will  be  recalled  that  counts  of  between  200,000  and 
300,000  cells  to  the  cubic  millimeter  are  the  rule,  but  in  the  lym- 
phatic form  it  is  only  in  comparatively  rare  instances  that  the 
estimate  exceeds  100,000.  Counts  of  500,000  or  even  of  1,000- 
000  cells  have,  it  is  true,  been  reported  by  a  few  observers,  but 
only  as  rare  examples  of  the  extreme  increase  which  it  is  pos- 
sible for  the  leucocytes  to  attain  in  this  condition.  The  cases  in 
Table  IX.  show  an  average  of  88,438  cells  to  the  cubic  milli- 


Table  IX. 

Number  of  Leucocytes  and  Percentage  of  Various   Forms  in   Lymphatic 
Leukemia,  at  the  First  Examination.     8  Cases. 


Leucocytes  per 
cb.  mm. 

Percentage  of  Different  Forms. 

No. 

Total  lym- 
phocytes. 

Small  lym- 
phocytes. 

Large  lym- 
phocytes. 

Polynuclear 
neutrophiles. 

Eosino- 
philes. 

Myelo- 
cytes. 

I 

120,000 

530 

aS.o 

25.0 

450 

2.0 

0.0 

2 

119,500 

97-7 

63.2 

34-5 

2.0 

0.0 

0-3 

3 
4 
5 
6 

115,000 
96,000 
88,000 
85,000 

90.0 
92.0 
89.0 
97.0 

330 
28.8 

25.2 
28.0 

57-0 
63.2 
63.8 
69.0 

9-9 
6.1 

5-6 

30 

O.I 
0.0 
0.5 
0.0 

0.0 

1.9 

4-9 
0.0 

7 

46,000 

97.3 

21. 1 

76.2 

1.6 

0.0 

I.I 

8 

38,000 

913 

21.3 

70.0 

7.1 

0.0 

1.6 

Av. 

88,438 

88.4 

311 

57-3 

lO.O 

0.3 

1.2 

LYMPHATIC    LEUKEMIA. 


259 


meter,  with  a  minimum  of  38,000,  and  a  maximum  of  120,000. 
It  may  be  noted  that  a  few  of  these  cases  showed  an  increase  not 
much  greater  than  can  be  found  in  a  high-grade  leucocytosis. 

By  examination  of  the  stained  film,  the  identity  of  the  leuco- 
cytes responsible  for  the  high  count  is  more  clearly  distinguish- 
able, and  it  is  found  that  the  increase  is  due  to  a  large  absolute 
gain  in  the  lymphocytes,  the  relative  percentage  of  these  cells  to 
the  other  varieties  of  leucocytes  generally  being  90,  or  95, 
or  even  higher.  In  the  series  above  summarized  (Table  IX.) 
these  non-granular  cells  averaged  88.4  per  cent,  of  the  leuco- 
cytes, and  equalled  or  exceeded  90  per  cent,  in  three-fourths  of 
the  cases  examined.  In  some  instances  the  small  lymphocytes 
are  found  to  be  in  excess,  and  the  field  is  dotted  with  small, 
deeply  stained  cells  ranging  from  about  5  to  10  />«  in  diameter; 
in  other  instances  the  larger  forms  prevail,  so  that  large,  feebly 
stained  cells,  from  about  10  to  1 5  />«,  or  even  larger,  are  in  excess  ; 
while  in  still  other  cases  the  sizes  and  staining  properties  of  the 
cells  are  so  variable  and  atypical  that  it  is  impracticable  to  class 
them  in  two  definite  groups,  large  and  small.  It  is  generally 
believed  that  small  lymphocytes  are  associated  with  the  more 
chronic  forms  of  the  disease,  and  that  the  larger  varieties  are 
found  in  excess  in  the  acute  cases.  Many  of  the  larger  forms, 
which  possess  a  relatively  large  nucleus  deficient  in  chromatin 
and  a  faintly  basic  non-granular  protoplasm,  are  regarded  as  the 
mother-cells  of  the  typical  small  lymphocytes.  They  are  iden- 
tical with  the  '' lymphogonien  "  of  Benda  and  the  *' leukoblasts" 
of  Lowit,  cells  resident  in  the  germinal  nests  of  the  lymphatic 
tissues.  In  the  triple  stained  specimen  they  bear  a  certain  re- 
semblance in  size  and  shape  to  the  myelocytes,  but  differ  from 
them  in  having  a  protoplasm  devoid  of  neutrophile  granules. 

Various  atypical  forms  of  lymphocytes,  the  commonest  of 
which  are  pictured  below  (Fig.  41),  are  often- numerous.  With 
basic  stains,  such  as  methylene-blue,  a  ragged,  torn  condition  of 

Fig.  41. 


I  2  3456 

Atypical  forms  of  lymphocytes  in  lymphatic  leukemia. 

I.  Large  lymphocyte  with  ragged  protoplasm.  Two  small  bits  of  protoplasm,  the  product  of 
"  budding,"  lie  free  in  the  plasma  beside  the  cell.  2.  Large  lymphocyte  showing  a  nucleolus,  3. 
Large  lymphocyte  containing  two  nuclei.  4.  Small  lymphocyte  containing  an  indented  nucleus.  5. 
Small  lymphocyte  containing  two  nuclei.  6.  Cell  the  size  of  a  large  lymphocyte,  with  the  nucleus  of 
a  small  lymphocyte,  (i  and  2  are  stained  with  eosm  and  methylene-blue,  3,  4,  5,  and  6  with  Ehrlich's 
triacid  stain.) 


26o  DISEASES    OF    THE    BLOOD. 

the  basic  seam  of  protoplasm,  and  so-called  "budding"  of  the 
protoplasm  are  frequently  demonstrable,  as  well  as  nucleolation  of 
some  cells,  especially  of  those  of  large  size.  Nuclear  indentation 
and  division,  and  forms  characterized  by  a  small  lymphocyte's 
nucleus  within  a  large  lymphocyte's  cell  body  are  also  common. 

The  relative  proportion  of  polyjiuclear  neutropJiiles  is  markedly 
diminished,  commonly  to  from  about  5  to  lo  per  cent,  of  the 
total  number  of  leucocytes,  and  sometimes  even  to  below  i  per 
cent.  These  cells  do  not  usually  display  the  abnormal  staining 
and  nuclear  characteristics  and  irregularities  in  size  and  shape 
that  are  so  often  seen  in  spleno-medullary  leukemia. 

Myelocytes  are  present  in  the  great  majority  of  cases,  but  al- 
ways in  trifling  numbers,  as  in  pernicious  anemia ;  their  propor- 
tion rarely  exceeds  i  or  2  per  cent,  of  all  forms  of  leucocytes. 

The  percentage  of  eosinophiles  is  diminished,  usually  to  a  frac- 
tion of  I  per  cent.,  and  in  a  certain  proportion  of  cases  these  cells 
are  absent  from  the  peripheral  blood.  It  must  be  remembered, 
however,  that  even  with  a  low  relative  percentage  figure  for  the 
eosinophiles,  true  eosinophilia  may  exist,  although  usually  not  to 
such  a  marked  degree  as  in  the  spleno-medullary  form  of  the 
disease.  One  per  cent,  of  eosinophiles  in  a  leucocyte  count  of 
100,000  means  1,000  eosinophiles  per  cubic  millimeter  of  blood, 
or  twice  the  maximum  number  found  in  the  normal  individual. 
Eosinophilic  myelocytes  are  rare,  but  they  occur  in  small  numbers 
in  an  occasional  case. 

Increase  in  the  number  of  basophiles  has  been  observed  only 
exceptionally,  and  both  the  finely  granular  basophilic  leucocytes 
and  the  typical  mast  cells  are  generally  conspicuous  by  their 
absence,  in  contrast  to  their  abundance  in  the  spleno-medullary 
variety  of  this  disease. 

From  the  above,  it  is  evident  that  in  lymphatic  leukemia  the 
increase  in  the  total  number  of  leucocytes  is  dependent  upon  a 
marked  absolute  gain  in  the  lymphocytes,  and  that  in  conse- 
quence of  this  enormous  influx  of  mononuclear  hyaline  forms, 
the  relative  percentages  of  the  other  leucocytes,  especially  of  the 
polynuclear  neutrophiles,  are  correspondingly  diminished. 

As  in  the  spleno-medullary  form,  the  number  of  blood  plaques 
is  usually  much  increased. 

This  term  has  been  applied  to  a  form  of  leu- 
AcuTE         kemia  which  pursues  a  rapid  course  suggestive 

Leukemia,     of  an  acute  infectious  process,  and  ends  fatally 

within  a  few  weeks  after  the  onset  of  the  acute 

symptoms.      Rapid,   progressive   enlargement   of  the    lymphatic 

glands  and  a  relatively  small  splenic  tumor,  associated  with  such 


LYMPHATIC    LEUKEMIA.  26 1 

clinical  features  as  rigors  and  irregular  pyrexia,  bone  pains,  ulcer- 
ative stomatitis,  a  decided  tendency  to  hemorrhages  from  the 
mucous  membranes  and  to  purpura,  serve  to  identify  this  rapidly 
fatal  variety  of  the  disease.  Some  authors  limit  the  duration  of 
acute  leukemia  to  six  weeks,  but  the  time  limit  proposed  by  Fraen- 
kel,^  four  months,  is  generally  accepted  as  being  more  appropriate. 

The  disease  is  a  rare  one,  for  probably  fewer  than  seventy-five 
authentic  cases  have  been  recorded  up  to  the  present  time,  al- 
though many  more  reputed  instances  have  been  pubHshed.  Eb- 
stein^  collected  seventeen  cases,  in  1889 ;  FraenkeP  published  the 
statistics  often,  in  1895  ;  Bradford  and  Shaw*  described,  in  1898, 
five  cases  coming  under  their  observation ;  and  Fussell,  Jopson 
and  Taylor,^  in  the  same  year,  published  a  collective  report,  em- 
bracing the  statistics  of  fifty-seven  cases  selected  as  representing 
all  the  true  examples  of  acute  leukemia  reported  during  the  past 
twenty-one  years.  Since  this  report  about  a  dozen  additional 
cases  have  been  described  by  various  observers. 

Beyond  stating  that  lymphemia  is  the  type  of  blood  character- 
istic of  acute  leukemia,  no  special  description  of  the  condition  of 
the  blood  is  necessary.  In  the  majority  of  cases  the  leucocyte 
increase  may  be  attributed  to  a  marked  gain  in  the  large  lympho- 
cytes, which  greatly  predominate  over  the  small  forms,  while  the 
polynuclear  neutrophiles,  myelocytes,  and  eosinophiles  are  rela- 
tively few  in  number.  As  a  rule,  the  more  acute  the  case,  the 
more  decided  the  predominance  of  the  large  lymphocytes,  which 
usually  show  well-marked  evidences  of  nuclear  and  protoplasmic 
degenerative  changes.  The  loss  of  hemoglobin  and  eiythrocytes 
is  generally  more  marked,  and  the  erythroblasts  are  more  numer- 
ous than  in  the  commoner  forms  of  chronic  lymphatic  leukemia. 

Acute  leukemia  may  begin  as  such,  or  either  the  chronic  lym- 
phatic or  spleno-medullary  form  may  develop  acute  symptoms, 
with  a  coincident  change  in  the  condition  of  the  blood,  but  this 
change  in  the  spleno-medullary  form  is  extremely  rare. 

The  development  of  an  acute  infectious  process 
Influence  of  in   a    leukemic    individual    commonly  provokes 
Acute  Inter-  striking  changes  in  the  behavior  of  the  leucocytes, 
CURRENT  In-    consisting  in  most  instances  in  a  decrease  of  their 
FECTiONS.       total  number  to  the  cubic  millimeter  of  blood,  as- 
sociated sometimes  with  an  increase  in  the  poly- 
nuclear variety  of  cells  and  a  relative  diminution  in  the  number 

^  Deut.  med.  Woch. ,  1895,  vol.  xxi.,  p.  639  et  seq. 

2Deut.  Archiv,  f.  klin.  Med.,  1889,  vol.  x'liv,,  p.  343. 

3  Loc.  cit. 

*Medico-Chirurg.  Trans.,  London,  1898,  vol.  Ixxxi.,  p.  343. 

5  Trans.  Assn.  Am.  Phys.,  Phila.,  1898,  vol.  xiii.,  p.  124. 


262  DISEASES    OF    THE    BLOOD. 

of  myelocytes.  At  other  times  there  is  practically  no  alteration 
in  the  relative  proportions  of  the  different  forms  as  they  existed 
in  the  leukemic  blood  prior  to  the  onset  of  the  compHcating  in- 
fection. Among  the  infectious  conditions  acting  in  this  manner 
on  the  leucocytes  are  abscess,  sepsis,  pneumonia,  influenza, 
mihary  tuberculosis,  and  erysipelas,  but  it  seems  that  rheumatic 
fever  has  no  such  effect.  Weil,^  who  has  studied  the  effects  of 
colon,  pneumococcus,  and  streptococcus  infections  in  both  forms 
of  leukemia,  comes  to  the  conclusion  that  the  most  powerful  in- 
fluence upon  the  blood-picture  is  exerted  by  streptococcus  infec- 
tions. Malignant  disease  is  also  capable  of  bringing  about  a  leu- 
cocyte decrease  characterized  by  a  relative  gain  in  polynuclear 
neutrophiles  at  the  expense  of  the  lymphocytes,  but  the  loss  does 
not  appear  to  be  so  decided  as  that  excited  by  a  specific  infec- 
tious process. 

Two  cases  reported  by  Fraenkel  ^  may  be  cited  to  illustrate  the 
extreme  decrease  which  the  leucocytes  may  suffer  under  such 
influences  and  the  rapidity  with  which  the  loss  may  take  place. 
In  one  of  this  author's  cases,  five  days  after  the  beginning  of  a 
staphylococcus  infection  the  patient's  leucocytes  began  to  fall, 
their  number  decreasing  from  89,000  to  6,000  within  a  period  of 
two  weeks  ;  while  in  a  second  case  the  count  fell  from  220,000 
to  1,200  within  a  few  days,  the  change  in  this  instance  also  being 
attributed  to  a  septic  process.  In  a  patient  with  spleno-medullary 
leukemia  and  septicemia,  reported  by  Kormoczi,^  the  leucocytes, 
which  numbered  100,000  per  cubic  millimeter  at  the  first  exami- 
nation, fell  to  3,000  on  the  day  of  death,  the  myelocytes  practic- 
ally disappearing  from  the  blood,  and  a  moderate  increase  in  the 
lymphocytes  occurring  during  the  last  few  days  of  life.  Eisen- 
lohr^  hds  recorded  a  similarly  marked  decrease  in  the  leucocytes 
in  the  same  type  of  the  disease,  the  complicating  infection  being 
enteric  fever  ;  Miiller'  has  observed  a  fall  from  109,000  to  6,800 
in  a  case  of  acute  leukemia  in  which  a  staphylococcus  infection 
had  developed  ;  and  a  number  of  other  writers  have  reported  ex- 
amples of  more  moderate  leucocyte  decreases  due  to  various  in- 
fectious diseases. 

Coincident  with  the  improvement  in  the  condition  of  the  blood, 
there  is  frequently  a  decrease  in  the  size  of  the  patient's  enlarged 
spleen  and  lymphatics,  the  period  during  which  the  leukemic 
condition  is  thus  bettered  and,  so  to  speak,  held  in  abeyance, 

1  Gaz.  hebdom.  de  med.  et  de  chir. ,  1900,   n.  s.,  vol.  v.,  p.  829. 

2Loc.  cit. 

3  Deut.  med.  Woch.,  1899,  vol.  xxv.,  p.  773. 

■•Virchow's  Archiv,,    1878,  vol.  Ixxiii.,  p.  56. 

sjahrb.  f.  Kinderheilk.,    1896,  vol.  xliii.,  p.  130. 


LYMPHATIC  LEUKEMIA.  263 

corresponding  to  the  duration  of  the  compHcating  infection,  for 
the  blood  gradually  regains  its  leukemic  type  and  the  glandular 
and  splenic  tumors  reappear,  as  recovery  from  the  intercurrent 
disease  takes  place. 

In  rare  instances  the  occurrence  of  an  infectious  disease  fails  to 
cause  a  decrease  in  the  leucocytes,  and  thus  to  destroy  the  leu- 
kemic picture,  but  on  the  contrary  increases  them,  by  superim- 
posing a  typical  polynuclear  neutrophile  leucocytosis,  which  re- 
mains during  the  existence  of  the  complicating  infection  the 
more  conspicuous  feature  of  the  blood.  The  writer  has  observed 
a  typical  illustration  of  such  a  change  in  a  case  of  spleno-medul- 
lary  leukemia,  in  which  within  ten  days  after  the  onset  of  a  com- 
pHcating  peritonitis,  the  leucocyte  count  rose  from  245,000  to 
400,000,  and  the  proportion  of  polynuclear  neutrophiles  from 
44.5  to  79  per  cent.,  while  the  percentage  of  myelocytes  fell 
from  20.5  to  8.  A  somewhat  similar  change  has  been  observed 
by  Miiller,^  in  a  patient  with  lymphatic  leukemia,  the  increase  in 
leucocytes  having  been  220,000,  and  the  gain  in  polynuclear 
neutrophiles  noteworthy. 

j^  The  following  blood-picture  is  characteristic  of 

the  spleno-meduUary  variety  of  leukemia  : 

Hemoglobin.  Decided  loss,  averaging  about  50  per  cent.  Color 
index  subnormal,  or  high. 

Erythrocytes.  Counts  average  about  3,000,000  per  cubic  milli- 
meter. 

Erythroblasts  very  numerous,  cells  of  the  normo- 
blastic type  predominating. 

Deformities  of  size  and  shape,  polychromatophilia, 
and  basophilic  stroma  degeneration  marked  in  cases 
with  severe  anemia. 

Leucocytes.  Increased  to  about  300,000  per  cubic  millimeter, 
counts  in  excess  of  this  figure  being  comparatively 
rare. 

Myelocytes  constitute  about  20  per  cent,  of  all 
forms. 

Relative  percentageof  polynuclear  neutrophiles  low. 
Relative  percentage  of  lymphocytes  very  low. 
Eosinophiles  absolutely,  sometimes  relatively,  in- 
creased. 

Basophiles  increased,  especially  the  mast  cells. 
Atypical  forms  of  neutrophiles  numerous. 

Plaques.  Increased. 

^Deut.  Archiv.  f,  klin.  Med.,  1892,  vol.  xlix.,  p.  47. 


264  DISEASES    OF    THE    BLOOD. 

In  lymphatic  leukemia  the  blood  changes  may  be  briefly  ex- 
pressed thus  : 

Hemoglobin.      Marked  loss,  averaging  about  75  per  cent.     Color 
index  low. 

Erythrocytes.     Counts  average  about  2,250,000  per  cubic  milli- 
meter. 

Erythroblasts  usually  scanty,  cells  of  the  normo- 
blastic type  predominating. 

Deformities  of  size  and  shape,  and  atypical  staining 
reaction  marked  in  relation  to  the  degree  of  anemia 
present. 

Leucocytes.        Increased  to  about   100,000  per  cubic  millimeter, 

counts  above  this  figure  being  rare. 

Lymphocytes  constitute  about  90  per  cent,  of  all 

forms. 

Relative  percentage  of  polynuclear  neutrophiles 

strikingly  low. 

Relative  percentage   of   eosinophiles  diminished ; 

rarely,  an  absolute  increase. 

Small  numbers  of  myelocytes  frequent. 

Basophiles  usually  not  increased. 

Atypical  forms  of  lymphocytes  numerous. 
Plaques.  Increased. 

In  dealing  with  the  differential  diagnosis  of  leukemia  it  is  nec- 
essary/ to  distinguish  the  spleno-medullary  from  the  lymphatic 
form,  and  also  to  differentiate  both  forms  of  the  disease  from  a 
number  of  other  conditions  which  may  present  either  somewhat 
similar  blood  findings,  or  which,  apart  from  the  condition  of  the 
blood,  may  have  closely  similar  clinical  manifestations.  Thus,  on 
the  one  hand,  leucocytosis  and  lymphocytosis  require  differentia- 
tion because  they  produce  changes  in  the  blood  which  may  be 
confused  with  leukemia ;  while,  on  the  other  hand,  we  must  dis- 
tinguish between  leukemia  and  Hodgkin's  disease,  splenic  anemia, 
and  a  number  of  conditions  causing  enlargements  of  the  spleen, 
neighboring  organs,  and  lymphatic  glands  because  of  the  resem- 
blance, even  identity  in  some  instances,  of  the  other  clinical 
signs. 

Splejw-medullary  and  lymphatic  Icukcjiiia  can  be  distinguihsed 
only  by  examination  of  the  blood,  for  the  distinction  between 
these  two  forms  of  the  disease  cannot  be  based  with  any  degree 
of  certainty  upon  the  gross  clinical  appearance  of  the  spleen  and 


LYMPHATIC  LEUKEMIA.  265 

lymphatics.  Nothing  can  be  more  marked  than  the  contrast  be- 
tween the  two  blood-pictures.  In  the  spleno-medullary  form  the 
leucocyte  count  is  usually  much  higher,  and  is  associated  with  the 
presence  of  immense  numbers  of  myelocytes,  and  with  an  increase 
in  the  eosinophils  and  usually  in  the  basophiles ;  the  oligocythe- 
mia is  not  so  marked,  but  erythroblasts  are  exceedingly  numerous, 
and,  strangely,  tend  to  persist  independently  of  any  increase  in  the 
erythrocytes  which  may  occur  from  time  to  time.  In  the  lym- 
phatic form  the  relatively  moderate  leucocyte  increase  depends 
upon  an  excessive  gain  in  the  ungranulated  cells,  or  lymphocytes, 
myelocytes  being  either  absent  or  present  in  trifling  numbers,  and 
decided  increase  in  the  eosinophiles  and  basophiles  being  most 
unusual ;  the  oligocythemia  is  usually  decided,  but  erythroblasts 
are  scanty,  and  stand  in  relationship  to  the  degree  of  anemia 
existing.  The  important  points  of  difference  are,  therefore,  the 
presence  of  a  myelocytic  blood  in  the  spleno-medullary  form, 
and  of  a  lymphocytic  blood  in  the  lymphatic  variety. 

Pathological  leiicocytosis  may  occasionally  involve  an  increase 
in  the  total  number  of  leucocytes  equal  to  that  found  in  either 
form  of  leukemia,  especially  in  those  cases  in  which  a  period 
of  temporary  improvement  with  a  fall  in  the  leucocyte  count 
exists.  But,  aside  from  the  more  or  less  temporary  character  of 
the  increase  in  leucocytosis,  the  differential  count  at  once  shows 
that,  unlike  leukemia,  the  gain  depends  upon  a  large  absolute  and 
relative  increase  in  the  polynuclear  neutrophiles,  which  constitute 
ordinarily  90  per  cent,  or  more  of  the  several  forms  of  leuco- 
cytes. 

Lymphocytosis,  which  is  usually  a  7'elative  condition,  may  in  rare 
instances  become  absolute,  so  that,  in  addition  to  the  increase  in 
the  relative  percentage  of  lymphocytes,  the  total  number  of  leu- 
cocytes in  the  blood  is  also  decidedly  increased.  In  marked  in- 
stances of  this  sort  it  is  obviously  impossible  to  distinguish  the 
blood  change  from  that  of  lymphatic  leukemia,  and  the  aid  of 
other  clinical  symptoms  must  be  invoked  to  make  the  diagnosis 
clear.  Thus,  both  an  absolute  and  relative  lymphocytosis,  closely 
simulating  the  lymphatic  form  of  leukemia,  have  been  observed  in 
severe  cases  of  chlorosis,  in  pertussis,  in  sarcoma  of  the  lymphatic 
structures,  and  in  acute  inflammatoiy  processes  occurring  in 
young  children.  The  author  recalls  an  instance  of  marked  abso- 
lute lymphocytosis  in  a  case  of  pernicious  anemia,  which  seemed 
to  justify  the  tentative  diagnosis  of  lymphatic  leukemia,  an  error 
which  was  later  corrected,  when  the  megaloblastic  blood-picture 
became  apparent.  In  such  instances,  which  are  fortunately  of 
very  rare  occurrence,  it  is  true  that  neither  the  percentage  of 


266  DISEASES    OF    THE    BLOOD. 

lymphocytes  nor  the  count  of  leucocytes  is  Hkely  to  average  as 
high  as  in  lymphatic  leukemia,  but  still  the  blood  changes  are 
sometimes  very  misleading,  and  should  not  be  reHed  upon  to  the 
exclusion  of  other  equally  important  symptoms. 

The  glandular  and  splenic  enlargements  of  Hodgkui  s  disease 
form  a  clinical  picture  identical  with  either  the  spleno-medullary 
or  the  lymphatic  variety  of  leukemia,  so  that  these  conditions  are 
distinguishable  only  by  the  result  of  the  blood  examination.  But 
by  this  means  the  diagnosis  is  made  extremely  simple,  by  finding 
in  Hodgkin's  disease  either  entirely  normal  blood  or  a  variable 
degree  of  anemia.  The  number  of  leucocytes  is  usually  nor- 
mal, except  in  cases  in  which  some  complicating  inflammatory 
or  infectious  process  causes  a  moderate  increase,  typical  of  a 
polynuclear  neutrophile  leucocytosis. 

The  rather  close  resemblance  which  certain  cases  of  splenic 
anemia  bear  to  leukemia,  together  with  the  points  of  difference 
between  these  two  diseases,  have  already  been  described.  (See 
page  235.) 

Enlargements  of  the  spleen,  left  kidney,  and  pancreas  may  lead 
to  the  inference  that  leukemia  exists.  Thus,  splenic  tumors  due 
to  chronic  malarial  infection,  to  amyloid  disease,  to  cysts,  and  to 
malignant  neoplasms  ;  enlargements  of  the  left  kidney  such  as 
can  be  caused  by  hydronephrosis,  by  cysts,  and  by  malignant 
disease ;  as  well  as  cystic  tumors  of  the  pancreas  and  malignant 
disease  of  the  retroperitoneal  glands  all  may,  on  physical  exami- 
nation, simulate  more  or  less  faithfully  the  leukemic  spleen.  The 
negative  character  of  the  blood  findings  will  at  once  exclude  leu- 
kemia, should  one  of  the  above-named  conditions  be  the  cause 
of  the  physical  signs  suggesting  this  disease. 

LympJiatic  hyperplasia,  due  to  tuberculosis,  to  syphilis,  and  to 
malignant  disease  may  also  be  mistaken  for  the  glandular  in- 
volvement of  leukemia,  for  such  enlargements  sometimes  show 
nothing  distinctive.  In  tuberculous  adenitis  the  blood  is  either 
normal,  or  anemic,  if  the  cachectic  state  of  the  patient  is  marked  ; 
or,  should  there  happen  to  be  a  secondary  infection  of  the  glands 
plus  the  tuberculous  lesions,  a  simple  polynuclear  leucocytosis 
is  found.  In  syphilitic  adenitis  there  is  often  anemia  with  a  mod- 
erate polynuclear  leucocytosis,  and  sometimes  with  a  relative 
lymphocytosis,  especially  in  children.  In  malignant  disease  of 
the  lymphatics  increase  in  the  number  of  leucocytes  may  also  be 
noted,  in  association  with  a  high-grade  anemia  ;  in  carcinoma  the 
increase  involves  chiefly  the  polynuclear  neutrophiles,  but  in  sar- 
coma the  lymphocytes  may  be  unduly  increased,  though  not  to 
the  extent  found  in  lymphatic  leukemia. 


hodgkin's  disease.  267 


VII.    HODGKIN'S   DISEASE. 

Nothing  characteristic  is  observed  either  in  the 
Appearance    gross  appearance  of  the  fresh  blood  drop,  or  in 
OF  THE        the  unstained  film,  microscopically.     The  blood 
Fresh  Blood,  may  appear  normal,  or   it   may  show  changes 
common  to  any  secondary  anemia. 
The  alkalinity  and  specific  gravity  of  the  whole  blood  are  di- 
minished in  relation  to  the  degree  of  anemia  which  exists.     Coag- 
ulation may  take  place  slowly,  or  even  be  as  incomplete  as  it  is 
reported  to  be  in  some  cases  of  leukemia  ;  or  it  may  occur  within 
the  normal  time  limit. 

The  hemoglobin   percentage  and  the  number 
Hemoglobin    of  erythrocytes  are  both  normal  in  the  early 
AND  stages  of  the  disease,  and  in  slowly  progressive 

Erythrocytes,  cases  the  blood  may  remain  unaffected  for  a  long 
period.  But  sooner  or  later,  as  the  disease  pro- 
gresses and  a  cachectic  condition  of  the  patient  develops,  anemia 
appears,  gradually  where  the  course  of  the  disorder  is  slow,  and 
rapidly  in  the  more  acute  forms.  Counts  made  when  the  patient 
first  comes  under  observation  usually  average  4,000,000  or  5,- 
000,000  cells  per  cubic  millimeter,  but  in  the  later  stages  the 
number  frequently  falls  to  one-half  this  figure  or  even  less.  The 
loss  of  hemoglobin  begins  earlier,  and  in  most  instances  is  pro- 
portionately somewhat  greater,  than  the  erythrocyte  decrease,  so 
that  subnormal  color  indices  rule — not  decidedly  low,  but  yet 
twenty  points  or  so  below  the  normal  standard.  In  cases  which 
develop  excessive  oligocythemia  the  index  figures  may  be  quite 
as  high  as  in  pernicious  anemia. 

In  the  series  of  10  cases  summarized  in  Table  X.,  the  hemo- 
globin averaged  somewhat  less  than  60  per  cent.,  ranging  be- 
tween 30  and  82  per  cent.;  the  erythrocyte  count  averaged 
3,853,700  per  cubic  millimeter,  the  minimum  being  2,207,000  and 
the  maximum  5,225,000,  with  one-half  the  cases  having  4,000,- 
000  cells  or  more ;  and  the  average  color  index  was  0.78,  or  from 
0.36  to  1. 17. 

Qualitative  changes  affecting  the  corpuscles  occur  in  relation 
to  the  intensity  of  the  anemic  process,  deformities  of  shape  and 
size  and  atypical  staining  reaction  of  the  cells  being  associated 
with  cases  in  which  notable  hemoglobin  and  erythrocyte  losses 
exist,  and  being  absent  when  the  anemia  is  moderate.  Nucle- 
ated erythrocytes  are  not  common,  nor  are  they  numerous  when 
present.  Usually  none  are  found,  except  in  connection  with  a 
high-grade  anemia,  under  which  circumstance  a  few  normoblasts 


268 


DISEASES    OF    THE    BLOOD. 


Table  X. 

Hemoglobin  and   Erythrocytes  in   Hodgkin's  Dise.ase,  at  the  First 
Examination,     io  Cases. 


Number. 

Hemoglobin 

Color  Index. 

Erj'throcytes  per 

Percentage. 

cb.  mm. 

I 

82 

.78 

5,225,000 

2 

So 

.78 

5,100,000 

3 

65 

.72 

4,500,000 

4 

30 

.36 

4,200,000 

5 

60 

•75 

4,000,000 

6 

46 

.66 

3,470,000 

7 

52 

.77 

3,360,000 

8 

50 

.76 

3,275,000 

9 

75 

1. 17 

3,200,000 

lO 

45 

1.02 

2,207,000 

Average  : 

58.5 

.78 

3.853.700 

may  be  detected,  and  in  rare  instances  an  occasional  megaloblast. 
In  the  average  case  the  leucocytes  are  normal, 
Leucocytes,    both  in  number  and  in  the  relative  percentage  of 
different    varieties.     More    rarely,    relative  lym- 
phocytosis   occurs,    involving  a    decrease    in    the    percentage   of 
polynuclear  neutrophiles,  but  not  increasing  the  total  number  of 
leucoc}tes.     An    instance    of  this  kind  has    been    observ^ed    by 
the  writer,   in  which  the  relative  proportion  of  lymphocytes  to 
other  forms  of  leucocytes  habitually  remained  for  some  months 
between   70  and   S^   per  cent.,  this  change  affecting  chiefly  the 
large  lymphocytes,  while  the  total   leucocyte  count   never  ex- 
ceeded normal. 

Table  XL 

Number  of  Leucocytes  and   Percentage  of  Various  Forms  in  Hodgkin's 
Disease,  at  the  First  Examination.     10  Cases. 


XT 

Leucocvtes  ner 

Percentage  of  Different  Forms. 

No.                ,    ■'        •"  - 
1          cb.  mm. 

t 

Small  Lym- 
phocytes. 

Large  Lym- 
phocytes. 

Polj-nuclear 
Neutrophiles. 

Eosinophiles. 

Myelocytes. 

I 
2 
3 

4 

5 
6 

7 
8 

9 
10 

21,000 

19,000 

16,000 

12,000 

11,900 

9.300 

7,000 

4,000 

3,600 

1,000 

5.5 

4.0 

27.2 

5.6 

23.0 

8.0 

29.5 

25.0 

18.I 

6.0 

4-5 
12.0 
12.8 
36.6 
12.0 
18.0 

145 

4.0 

30 
16.0 

89.0 
81.6 
58.8 

56.3 
64.0 

71.0 
530 
68.0 

75-6 
76.0 

I.O 

1.6 
1.2 

1-5 

I.O 

30 
3-0 
2.0 

2-5 

2.0 

0.0 

0.8 
0.0 
0.0 

ao 
0.0 
0.0 

I.O 

0.8 
0.0 

Av.  '        10,480 

151 

^3-3 

69-3 

1.8 

0.26 

hodgkin's  disease.  269 

If  secondary  infection  takes  place,  it  soon  becomes  evident  by 
an  increase  in  the  leucocytes  to  about  20,000  or  more,  principally 
involving  the  poly7mclear  netitrophile  cells,  at  the  expense  of  the 
lymphocytes — a  picture  of  typical  leucocytosis.  In  some  in- 
stances, however,  without  any  apparent  signs  of  a  secondary  in- 
fection or  of  a  glandular  inflammation,  the  total  count  may  ex- 
ceed the  normal  standard  by  several  thousand  cells,  and  yet  show 
a  normal  or  even  somewhat  increased  proportion  of  lymphocytes. 
Should  the  anemia  be  very  marked,  pronounced  leucopenia  is 
commonly  associated  with  it.  In  the  present  series  (Table  XI.) 
one-half  of  the  cases  showed  leucocyte  counts  above,  and  the 
other  half  below,  10,000  cells  to  the  cubic  millimeter,  the  highest 
estimate  being  21,000,  the  lowest  1,000,  and  the  average  10,480. 

Small  numbers  of  myelocytes  are  not  uncommon  in  the  ad- 
vanced anemia  of  Hodgkin's  disease,  but  they  are  never  more 
numerous  than  in  any  other  condition  accompanied  by  a  similar 
deterioration  of  the  blood. 

Small  numbers  and  low  percentages  of  eosinophiles  are  the 
rule,  both  in  cases  with  and  without  leucocytosis ;  it  is  most  un- 
usual for  these  cells  to  attain  the  maximum  normal  figure,  and 
they  are  sometimes  wholly  absent. 

Neither  the  finely  granular  basophiles,  nor  the  typical  mast  cells 
are  increased  in  this  disease. 

As  in  both  forms  of  leukemia,  the  number  of  blood  plaques  in 
Hodgkin's  disease  is  usually  increased. 

Although  no  characteristic  blood  changes    oc- 
DiAGNOSis.    cur   in    this  condition,  the  alterations  most  com- 
monly   observed    may  be  briefly  summed  up  as 
follows  : 

Hemoglobin.  Normal  in  the  early  stages  of  the  disease  ;  later,  a 
moderate  decrease,  estimates  averaging  about  60 
per  cent.  Color  index  commonly  subnormal, 
rarely  high. 

Erythrocytes.  Normal  in  the  early  stages  ;  later,  a  variable  degree 
of  oligocythemia,  counts  averaging  about  3,750,- 
000  per  cubic  millimeter. 

Erythroblasts  uncommon,  and  scanty  when  present. 
Normoblasts  prevail  almost  exclusively,  megalo- 
blasts  being  very  rare. 

Deformities  of  size  and  shape,  polychromatophilia, 
and  basic  stroma  degeneration  only  in  cases  with 
high-grade  anemia. 


2/0  DISEASES    OF    THE    BLOOD. 

Leucocytes.         Normal,  or  moderately  increased. 

Either  polynuclear  neutrophiles   or  lymphocytes 

may  be  relatively  increased,  more  commonly  the 

former. 

Small  numbers  of  myelocytes  in  greatly  anemic 

cases. 

Eosinophiles  not  increased. 

Basophiles  not  increased. 

Plaques.  Usually  increased. 

The  absence  of  characteristic  blood  changes  in  Hodgkin's 
disease  at  once  distinguishes  the  condition  from  its  clinical  coun- 
terfeit, leukemia,  but  aside  from  this  single  disease,  the  blood  ex- 
amination is  valueless  in  the  differentiation  of  other  conditions 
having  somewhat  similar  involvement  of  the  glandular  structures. 
These  conditions,  tuberculous  and  syphilitic  adenitis,  local  lyiupho- 
inatous  tumors,  and  malig7iant  neoplasms  of  the  lymphatics,  must 
therefore  be  distinguished  from  Hodgkin's  disease  by  other  clin- 
ical methods,  for  they  all  may  provoke  identical  blood  changes. 

In  reviewing  the  clinical  history  of  a  case  of  suspected  Hodg- 
kin's disease,  the  following  symptoms  should  be  given  special 
consideration  :  the  gradual  onset  of  a  widespread  hyperplasia  of 
the  lymphatic  structures,  occurring  most  commonly  in  males 
under  middle  age  ;  the  progressive  character  and  chronicity  in 
most  cases  of  the  disorder ;  the  tendency  in  some  cases  toward 
the  occurrence  of  unexplained  febrile  periods,  sometimes  coincid- 
ing with  a  rapid  and  marked  increase  in  the  size  of  the  affected 
glands  which  disappears  as  the  fever  subsides  ;  the  cachexia, 
asthenia,  and  emaciation  of  the  patient,  frequently  associated  with 
gastro-intestinal  and  circulatory  disturbances,  and  with  a  tendency 
to  hemorrhages,  such  as  epistaxis  and  purpura  ;  the  presence  of 
pressure  symptoms,  such  as  cough,  dysphagia,  dyspnea,  edema, 
and  pleural  and  peritoneal  effusions  ;  and  the  development  of 
bronzing  of  the  skin  in  an  occasional  case. 

In  typical  cases,  the  glandular  enlargement  forms  a  series  of 
distinct,  painless,  hard  tumors,  each  freely  separable  from  its 
neighbor,  and  rarely  caseating  or  suppurating.  Due  weight 
should  also  be  given  to  the  fact  that  in  the  majority  of  cases  the 
lesion  originates  in  the  superficial  lymphatic  glands  of  the  cervical 
region,  beginning  either  in  the  occipital  or  in  the  inferior  carotid 
triangle.  The  spleen  is  moderately  enlarged  in  the  majority  of 
cases,  and  in  others  the  liver,  kidneys,  suprarenals,  tonsils, 
thymus,  thyroid,  and  sexual  organs  may  be  involved  in  the 
lymphoid  growths. 


HODGKIN  S    DISEASE.  2/1 

Ttibercidous  adenitis  usually  first  involves  a  group  of  glands  in 
the  submaxillary  triangle,  and  tends  to  produce  inflammatory 
adhesions  between  the  tissues  and  the  glandular  structure,  and 
softening,  fusing,  caseation,  and  suppuration  of  the  glands.  It  is 
of  sluggish  development,  often  occurs  in  the  very  young,  and  is 
almost  always  confined  to  a  single  group  of  glands.  Evidences 
of  tuberculous  lesions  in  the  lungs  or  in  other  parts  of  the  body, 
especially  of  dental  caries,  cutaneous  lesions  of  the  face,  and  ade- 
noid pharyngeal  growths,  and  the  discovery  of  tubercle  bacilH  in 
the  glandular  tissue  are  valuable  evidences  of  the  tuberculous 
nature  of  the  disease,  yet  they  do  not  positively  exclude  Hodg- 
kin's  disease,  since  the  coexistence  of  the  two  conditions  in  the 
same  individual,  although  rare,  is  possible  beyond  a  doubt. 

In  syphilitic  adenitis  of  the  neck  the  post-cervical  groups  are 
first  affected,  the  glands  being  of  cartilaginous  hardness,  painless, 
freely  movable,  and  of  small  or  moderate  size.  The  glandu- 
lar enlargement  is  often  more  or  less  general,  but  the  affected 
groups  do  not  attain  a  large  size.  A  history  of  an  initial  lesion 
in  the  vicinity  of  the  primary  glandular  swellings,  or  of  the 
appearance  of  secondary  symptoms,  the  disappearance  of  the 
glandular  tumors  after  the  administration  of  mercury,  and  the 
presence  of  Justus'  test  will  suffice  to  prove  the  specific  character 
of  the  hyperplasia. 

A  local  lymphoma  is  limited  strictly  to  a  single  group  of  glands, 
forming  a  painless,  dense  mass,  free  from  inflammatory  adhesions, 
caseation,  and  suppuration.  It  commonly  involves  the  submaxil- 
lary glands,  may  attain  a  large  size,  and  is  unassociated  with  con- 
stitutional symptoms.  Such  a  local  lymphatic  tumor  cannot  be 
distinguished  from  the  early  stage  of  Hodgkin's  disease,  for  in 
some  cases  of  the  latter  the  general  lymphoid  hyperplasia  is  pre- 
ceded by  a  period  during  which  the  only  sign  of  the  condition  is 
a  localized  enlargement  of  a  single  group  of  glands.  If,  accord- 
ing to  Osler,^  a  local  glandular  tumor  of  this  kind  persists  for 
over  a  year  or  eighteen  months  without  involving  the  glands  of 
the  opposite  side  or  of  the  axilla,  it  is  almost  certainly  a  non- 
malignant  lymphoma. 

Saj'coma  of  the  lymphatic  tissue  forms  an  immovable  tumor, 
early  complicated  by  inflammatory  processes  which  cause  inter- 
glandular  adhesions  and  adhesions  between  the  glands  and  the 
surrounding  tissues.  The  swelling  is  often  red  and  inflamed,  pits 
upon  pressure,  and  resembles  an  abscess,  while  the  skin  over  the 
site  of  the  lesion  is  frequently  marked  by  a  maze  of  tortuous, 
congested,  cutaneous  veins,  and  is  prone  to  ulcerate.     The  adja- 

1  Cited  by  Bramwell :  "Anemia,"  etc.,  Phila.,  1899,  p.  203. 


2/2  DISEASES    OF    THE    BLOOD. 

cent  tissues  become  densely  infiltrated  by  the  sarcomatous  growth, 
and  involvement  of  distant  organs  by  metastasis  is  likely  to  occur. 
If  nerves  are  entangled  in  the  growth,  the  tumor  is  exquisitely 
painful.  Sarcoma  of  the  lymphatic  glands  may  occur  at  any 
period  of  life. 

Carcinoma  of  the  lymphatic  glands  is  secondary  to  an  initial 
growth  in  some  other  part  of  the  body,  so  that  in  the  region  of 
the  neck  search  should  be  made  for  a  primary  cancerous  lesion 
in  the  mouth  and  upper  air  passages.  The  disease  is  most  com- 
monly found  during  the  decline  of  life. 

Finally,  as  Tyson  so  pertinently  remarks,^  it  should  not  be  for- 
gotten that  all  the  conditions  named  as  possible  to  be  mistaken 
for  Hodgkin's  disease  are  limited  to  a  single  group  of  glands, 
while  Hodgkin's  disease  always  extends,  and  the  fact  of  such 
limitation  is  of  itself  sufficient  to  preclude  the  disease.  This  pro- 
gressive involvement  of  the  lymphatic  glands,  group  after  group, 
must,  after  all,  be  our  mainstay  in  the  diagnosis  of  doubtful  cases 

VIII.     THE   EFFECT  ON   THE   BLOOD  OF   SPLENEC- 
TOMY. 

Excision  of  the  spleen  in  man  is  followed  by  a 
Hemoglobin    diminution  in  the  hemoglobin  and  ery-throcytes, 
AND  the  degree  of  which  is  generally  believed  to  be 

Erythrocytes,  more  pronounced  than  can  be  accounted  for  by 
the  simple  factor  of  hemorrhage  incident  to  the 
operation.      Blood  regeneration  is  slow,  especially  the  restoration 
of  the  hemoglobin,  which  is  prone  to  increase  much  less  rapidly 
than  is  the  rule  in  an  ordinary  secondary  anemia.      In  uncompli- 
cated cases    from  one  to  three  months'  time  usually  elapses  be- 
fore the  normal  percentages  of  hemoglobin  and  er>^throcytes  are 
attained  ;    in   unfavorable  cases  persistence  of  the  anemia  for  a 
much  longer  period  is  to  be  observed.     Splenectomies  attended 
by  great  loss  of  blood  may  excite,  in  addition  to  an  extreme  cel- 
lular decrease,  striking  qualitative  changes,  and  in  such  instances 
the  blood-picture  is  characterized  by  the  presence  of  many  normo- 
blasts, achromacytes,  and  corpuscles  deformed  in  shape  and  size. 
Conspicuous  post-operative  anemia  is  especially  common  in  pa- 
tients to  whom  saline  intravenous  injections  have  been  administered. 
Post-operative  leucocytosis  of  the  polynuclear 
Leucocytes,    neutrophile  type  develops  promptly,  and  persists 
in  most  instances  for  from  four  to  six  weeks,  ac- 
cording to  Hartmann  and  Vaquez,^  but  occasionally  for  a  longer 

I  "  Practice  of  Medicine,"  Phila.,  1898,  p.  606. 
2Compt.  rend.  Soc.  bioL,  Paris,  1897,  voL  iv.,  p.  126. 


THE  EFFECT  ON  THE  BLOOD  OF  SPLENECTOMY. 


273 


period.     Counts  of  between  1 5 ,000  and  30,000  represent  the  grade 
of  leucocytosis  ordinarily  found,  although  occasionally  the  increase 


Table  XII. 

The  Effect  on  the  Blood  of  Splenectomy. 


si 

a 
12 

tn 

V 

S 

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CO 

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^ 

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II 

65 

5,200,000 

2,200 

22 

5 

70 

3 

Before  operation. 
Megaloblasts   and    nor- 
moblasts found. 

^5 

5,000,000 

24,000 
21,400 

23,800 

18,000 
1 8,000 

3'(^ 

3-2 

93 

.2 

2  days  after  operation. 

4  <<         '<                «' 

5  "      "           " 

8       "         "               a 

45 

3,256,000 

24,000 
16,400 

7.9 

8.5 

81 

2.6 

II       <<        a              a 
Myelocytes     and     mast 

cells  found.    No  eryth- 

roblasts. 
16  days  after  operation. 

4i> 

4,496,000 

17,000 

7.8 

9 

76.8 

6.2 

21      "       <<           «< 
Myelocytes, .  2  per  cent. 

40 

3,984,000 

20,000 

9 

7-4 

82.2 

1.4 

27  days  after  operation. 
No  erythroblasts. 

40 

4,000,000 

15,000 

5.8 

7.4 

82.8 

4 

37  days  after  operation. 

52.5 

4,672,000 

21,600 

151 

«t 

731 

2 

56     "        *'           '< 
Myelocytes   found  ;    no 
erythroblasts. 

16,000 

51 

loi 

79| 

3.5 

99  days  after  operation. 
Erythrocytes  normal. 

22 

108 

4,850,000 

30,000 

8 

8 

83 

I 

Before  operation. 

100 

4,700,000 

39,000 

5 

4 

91 

0 

7  days  after  operation. 

105 

3,630,000 

18,000 

15 

6 

7« 

I 

60     "        <'           << 

03 

2,750,000 

20,000 

5 

10 

84 

I 

3  years      *'           << 

3' 

45 

1,634,000 

12,000 

16 

20 

61 

3 

14  days      *'           << 

i^7 

2,460,000 

20,000 

18 

32 

49 

I 

27     <<        «<            *< 

no 

4,530,000 

27,000 

18 

IS 

66 

I 

33     " 

100 

3,977,000 

8,000 

21 

II 

62 

6 

2  years  and  six  months 
after  operation. 

4* 

63 

4,570,000 

8,000 

Before  operation. 

64 

4,970,000 

30,000 

3  days  after  operation. 

77 

5,180,000 

65,000 

5     ((        <<           << 

66 

4,800,000 

17,500 

48     '*        <<           '< 

^5 

4.353,000 

11,700 

4  months'*           " 

85 

3,300,000 

11,600 

5  years     **           " 

1  Warren  :  Annals  of  Surgery,  1901,  vol.  xxxiii.,  p.  513. 

2  Hartman  and  Vasquez  :  loc.  cit. 

3  Ibid. 

*Czerny,  cited  by  Vulpius  :  Beitrage  z.  klin.  Chir.,  1894,  vol.  xi.,  p.  633. 
18 


2/4  DISEASES    OF    THE    BLOOD. 

is  far  greater — 70,000  in  a  case  cited  by  Czerny,^  and  75,000  in 
one  reported  by  Hartley."  After  a  number  of  months  (usually 
some  time  during  the  second  or  third  year  after  the  operation), 
there  is  a  moderate  increase  in  the  number  of  eosinophiles.  In 
splenectomized  guinea-pigs  Kurloff^  found  during  the  first  year 
after  the  operation  a  marked  lymphocytosis,  as  high  as  60  per 
cent,  in  some  animals,  together  with  a  corresponding  decrease  in 
the  number  of  granular  cells,  but  with  no  alteration  in  the  num- 
ber of  large  mononuclear  leucocytes.  Eosinophilia  became  ap- 
parent during  the  second  year,  and  coincident  with  this  change 
a  decrease  in  the  lymphocytes  to  their  normal  percentage  took 
place. 

The  above  remarks  concerning  the  differential  changes  affect- 
ing the  leucocytes  after  splenectomy  must  be  regarded  as  tenta- 
tive, in  view  of  the  fact  that  sufficient  data  bearing  upon  this 
question  have  not  yet  accumulated  to  justify  more  definite  con- 
clusions. 

The  table  on  page  273  shows  the  condition  of  the  blood  in  the 
few  recorded  cases  in  which  pre-  and  post-operative  examinations 
have  been  carried  out. 

It  is  to  be  remembered  that,  aside  from  the  character  of  the 
splenic  lesion,  these  important  factors  also  determine  the  degree 
of  the  post-operative  anemia  and  leucocytosis  in  this  procedure  : 
the  grade  of  the  preexisting  anemia,  the  amount  of  hemorrhage 
during  and  following  operation,  and  the  patient's  recuperative 
powers.  All  things  being  equal,  the  anemia  is  least  marked  and 
the  blood  regeneration  most  prompt  in  simple  zuandering  spleen 
and  in  ague  cake,  while  blood  deterioration  is  more  marked  and 
regeneration  slower  in  niptiire  of  this  organ.  Splenectomy  for 
sple7io-viediillary  leukemia  is  almost  invariably  followed  by  a  pro- 
gressive anemia  and  leucocytosis,  and  in  nearly  all  cases  by  death. 
But  five  recoveries  after  removal  of  the  spleen  in  this  disease 
have  been  reported  up  to  the  present  time.^ 

^  Loc.  cit. 

^Med.   News,  1898,  vol.  Ixxii.,  p.  417. 
3  Cited  by  Ehrlich,  loc.  cit. 

*  Hagen  :  Archiv.  f.  klin.  Chir.,  1900,  vol.  v.,  p.  188.  Also,  Richardson,  cited 
by  Warren  :  loc.  cit. 


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SECTION   VI. 


THE  ANEMIAS   OF   INFANCY  AND   CHILDHOOD. 


SECTION   VI. 
THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 


I.    CHARACTERISTICS  OF  THE  BLOOD  IN  CHILDREN. 

As  a  preliminary  essential  to  the  intelligent 
Fetal  Blood,  study  of  the  various  pathological  conditions  of 
the  blood  in  children,  it  is  necessary  briefly  to 
refer  to  certain  points  of  difference  in  the  composition  of  this  tis- 
sue in  the  child  and  in  the  adult.  In  general  terms,  it  may  be 
stated  that  the  younger  the  child  the  more  unformed  are  the 
different  elements  of  the  blood  and  the  nearer  its  composition 
resembles  the  blood  of  the  fetus. 

In  fetal  blood  the  specific  gravity,  both  of  the  whole  blood  and 
of  the  serum,  is  lower  than  in  the  adult,  and  coagulation  is  very 
slow.  The  erythrocytes  vary  greatly  in  size  and  in  shape,  and 
are  deficient  in  hemoglobin,  which  is  loosely  attached  to  these 
cells,  and  hence  becomes  readily  dissolved  out. 

Until  about  the  seventh  month  of  intra-uterine  life  normo- 
blasts constitute  the  predominating  variety  of  erythrocytes,  after 
which  period  they  rapidly  diminish  in  number,  until  at  full  term 
few,  if  any,  nucleated  red  corpuscles  are  found  in  the  blood.  Of 
the  different  varieties  of  leucocytes,  the  mononuclear  fornis  are 
present  in  a  proportion  relatively  excessive  to  the  other  varieties ; 
before  the  seventh  month  this  lymphocytosis  is  due  to  a  high 
relative  percentage  of  large  lymphocytes,  but  after  this  period 
the  proportion  of  small  lymphocytes  increases,  until  finally 
the  latter  type  of  cells  predominates.  The  percentage  of 
eosinophiles  reaches  its  maximum  at  the  seventh  month,  gradu- 
ally becoming  less  and  less  as  the  end  of  the  intra-uterine  life 
approaches. 

We  find,  therefore,  that  in  the  fetus  the  blood  is  characterized 
chiefly  by  the  presence  of  large  numbers  of  normoblasts,  by  a 
high  relative  proportion  of  mononuclear  leucocytes,  and  by  a  de- 
ficiency of  hemoglobin.  The  closer  an  infant's  blood  resembles 
this  picture,  the  ''younger"  in  point  of  development  is  such 
blood  considered,  and  the  more  strongly  is  it  said  to  revert  to  a 
''young"  or  "embryonal"  type. 


28o  THE    ANEMIAS    OF    INFANCY    AND    CHILDHOOD. 

At  birth,  the  blood  of  the  full-term  infant  is  of 

The  Blood  higher  specific  gravity,  and  richer  in  hemoglobin 
AT  Birth.  and  in  corpuscular  elements  than  that  of  the  older 
child  or  of  the  adult. 

The  specific  gravity  of  the  blood  of  the  average  healthy  infant 
at  the  time  of  birth  and  during  the  first  few  weeks  of  life  is,  ap- 
proximately, 1066.  For  normal  children  the  average,  which  is 
reached  by  the  beginning  of  the  second  year,  varies  from  1050  to 
1058,  being  slightly  higher  in  boys  than  in  girls. 

The  maximum  amount  of  hemoglobin  is  found  at  birth,  the  per- 
centage at  this  time  ranging  from  100  to  104,  according  to  the 
investigations  of  Hammerschlag.^  After  birth  the  amount  of 
hemoglobin  immediately  begins  to  diminish,  the  minimum,  which 
may  be  as  low  as  55  or  60  per  cent.,  being  attained  by  the  end 
of  the  third  week  of  life.  It  remains  at  or  about  this  minimum 
for  a  variable  period  of  time,  sometimes  for  as  long  as  six  months, 
and  then  gradually  begins  to  increase. 

At  birth,  the  number  of  erythrocytes  in  the  peripheral  blood  is 
decidedly  higher  than  normal,  counts  of  between  5,500,000  and 
6,000,000  cells  per  cubic  millimeter  being  found  at  this  time,  the 
highest  figures  being  observed  in  those  cases  in  which  ligation  of 
the  umbilical  cord  has  been  delayed.  During  the  first  twenty- 
four  hours  of  extra-uterine  life  this  polycythemia  becomes  still 
more  marked,  so  that  the  number  of  corpuscles  per  cubic  milli- 
meter may  reach  a  maximum  of  from  7,000,000  to  8,000,000, 
and  sometimes  more,  by  the  end  of  the  first  day.  Beginning  with 
the  second  day,  a  gradual  diminution  in  the  number  of  these  cells 
is  noticed,  and  the  normal  5 ,000,000  per  cubic  millimeter  is  reached 
by  the  end  of  the  first  week  or  ten  days.  Hayem  ^  emphasizes  the 
fact  that  the  fluctuations  in  the  number  of  erythrocytes  during  the 
early  days  of  life  stand  in  inverse  ratio  to  the  variations  in  the 
weight  of  the  child,  the  maximum  number  being  found  at  the 
time  of  the  infant's  minimum  weight,  while  as  the  child  begins  to 
gain  in  weight  the  count  decreases.  Schiff  ^  is  inclined  to  attrib- 
ute these  fluctuations  to  the  amount  of  liquids  in  the  body,  the 
result  of  feeding,  showing  that  in  fasting  children  the  counts  are 
always  higher  than  in  those  fed  at  frequent  inter\^als. 

Whatever  may  be  the  exact  manner  of  their  production,  it  is 
evident  that  these  fluctuations  are  to  be  regarded  as  purely  physio- 
logical in  character,  depending  upon  concentration  and  dilution  of 
the  blood,  rather  than  as  an  expression  of  involvement  of  the 
blood-making  organs. 

1  Centralbl.  f.  klin.  Med.,  1891,  vol.  xii.,  p.  825. 
2"Du  Sang,"  etc.,  Paris,  1889. 
^Zeitschr.  f.  Heilk.,  1890,  vol.  xi.,  p.  17. 


CHARACTERISTICS    OF    THE    BLOOD    IN    CHILDREN. 


281 


The  erythrocytes  vary  greatly  in  size  during  the  first  few  days 
of  post-natal  life,  the  diameter  of  some  cells  being  as  small  as 
3.25  /z,  and  of  others  as  large  as  10.25  ft.  Many  observers  have 
noticed  that  the  small-sized  cells,  as  a  rule,  predominate. 

Nucleated  erytJirocytes  of  the  normoblastic  type  may  or  may 
not  be  present  in  the  blood  of  new-born  infants  ;  they  are  com- 
monly found  in  large  numbers  in  the  prematurely  born  child,  and 
also  occur  less  numerously  in  many  fully  developed  babies,  not- 
withstanding views  to  the  contrary  expressed  by  some  observers, 
notably  by  Hayem  ^  and  by  Fischl.^  In  most  cases  normoblasts 
disappear  from  the  blood  after  the  first  few  days  of  life,  and  their 
presence  after  the  sixth  month  should  always  be  regarded  as  pa- 
thological. 

The  number  of  leucocytes  at  birth  averages  about  20,000  per 
cubic  miUimeter,  the  normal  average  for  young  infants,  15,000 
per  cubic  miUimeter,  being  reached  by  the  end  of  the  first  week, 
after  numerical  fluctuations  similar  to  those  affecting  the  erythro- 
cytes. From  the  second  or  third  week  until  the  sixth  month,  a 
count  from  10,000  to  14,000  may  be  regarded  as  normal,  while  for 
the  child  of  one  year  of  age  the  average  is  about  10,000.  By  the 
sixth  year  the  number  of  leucocytes  falls  to  the  number  normal 
for  the  adult,  7,500  per  cubic  millimeter.  The  following  excel- 
lent table  from  Rotch,^  shows  these  average  counts  of  erythrocytes 
and  leucocytes  in  children  from  birth  until  the  sixth  year  of  age  : 


Age. 

Erythrocytes. 

Leucocytes. 

At  birth. 

5,900,000 

21,000  (26,000  to  36,000 
after  first  feeding). 

End  of  1st  day. 

7,000,000  to  8,000,000 

24,000 

"       2d    '* 

Generally  increased. 

30,000 

"      4th   " 

6,000,000 

20,000 

"      7th   " 

5,000,000 

15,000 

loth  day. 

10,000  to  14,000 

1 2th  to  1 8th  day. 

12,000 

1st  year. 

10,000 

6th  year  and  upwards. 

7,500 

The  influence  of  the  initial  feeding  in  infants  produces  a  marked 
leucocytosis,  the  increase  amounting  to  from  5,000  to  15,000 
cells  per  cubic  millimeter,  as  shown  by  the  above  table.  It  is 
probable  that  the  habitual  leucocytosis  of  early  childhood  is 
largely  referable  to  a  more  or  less  continuous  digestion  leucocy- 
tosis. (For  a  further  discussion  of  this  question  see  **  Digestion 
Leucocytosis,"  page  179.) 

^  Log.  cit. 

2Zeitschr.  f.  Heilk.,  1892,  vol.  xiii.,  p.  277. 

3 ''Pediatrics,"  etc.,  Phila.,  1896,  p.  342. 


282       THE  ANEMIAS  OF  INFANCY  AND  CHILDHOOD. 

The  blood  of  infants  and  of  young  children  differs  greatly  from 
that  of  the  adult  in  the  relative  proportions  of  the  different  forms 
of  leucocytes,  these  qualitative  differences  becoming  less  and  less 
apparent  as  the  child  grows  older,  and  not  usually  persisting 
beyond  the  tenth  year.  In  general  terms,  it  may  be  said  that 
these  dissimilarities  are  striking  in  relation  to  the  youth  of  the 
child.  Compared  to  the  adult,  a  differential  count  of  the  leuco- 
cytes in  the  child  shows  that  the  relative  percentage  of  lympho- 
cytes is  more  than  twice  as  great,  and  of  polynuclear  neutrophiles 
one-half  as  great,  while  the  proportion  of  eosinophiles  is  fre- 
quently much  higher.  In  the  following  table,  based  upon  data 
given  by  Gundobin,^  these  points  of  difference  are  contrasted: 

Forms  of  Leucocytes.  Infants.  Advlts. 

Small  lymphocytes.      50      to  70  per  cent.      20      to  30  per  cent. 
Large  lymphocytes, 
and  transitional 


forms. 

6       ''  14 

( ( 

4       ''     8 

Polynuclear  neutro- 

philes. 

28        ''  40 

n 

60       -  75 

Eosinophiles. 

0.5    ''  10 

I  i 

0.5   "     5 

It  is  important  to  take  into  account  these  differences,  in  mak- 
ing blood  examinations  in  children,  in  whom  we  must  expect  to 
find  percentages  of  lymphocytes  which  in  the  adult  would  be 
regarded  as  abnormally  high. 

Lcucocytosis  in  children  is  of  extremely  common  occurrence, 
often  arising  from  causes  of  the  most  trivial  character,  and  de- 
veloping to  a  greater  degree  and  with  much  more  rapidity  than 
in  the  adult.  It  is  therefore  to  be  regarded  with  less  significance 
than  when  it  occurs  in  the  mature.  Usually  the  polynuclear  cells 
are  chiefly  involved  in  the  increase,  but  the  inclination  of  the 
blood  of  children  to  revert  to  the  embryonic  type  appears  to 
cause,  in  many  cases,  a  disproportionate  increase  of  lymphocytes 
in  relation  to  the  other  forms,  this  peculiarity  being  especially 
true  of  the  various  pathological  leucocytoses.  Physiological  leu- 
cocytosis  in  children  usually  affects  chiefly  the  polynuclear  neu- 
trophile  cells. 

II.      ANEMIA    IN   CHILDREN. 

Children,  as  a  class,  are  peculiarly  susceptible 
Frequency,    to  anemia,  for  they  appear  to  lack  resisting  pow- 
ers against  the  influence  of  causes  tending  to  pro- 
duce pathological  alterations  in  the  blood.     Thus,  it  is  found  that 
the  same  factors  which  in  the  adult  have  little  or  no  effect  upon 

^Jahrb.  f.  Kinderheilk.,  1893,  vol.  xxxv.,  p.  1S7. 


ANEMIA    IN    CHILDREN.  283 

the  blood  are  capable  of  producing  profound  alterations  in  its 
composition  in  the  child.  Severe  anemias  may  arise  in  children 
from  apparently  the  most  trivial  sorts  of  causes ;  slight  hemor- 
rhage from  the  navel,  for  instance,  may  light  up  an  anemia  of  an 
intensity  out  of  all  proportion  to  the  actual  amount  of  the  blood 
loss,  while  minor  lesions  of  the  gastro-intestinal  tract  are  com- 
monly associated  with  blood  deterioration  of  a  severe  type. 

It  is  a  notable  fact  that  in  anemic  children  a 
General      predominant  tendency  exists  toward  a  reversion 

Character-  of  the  blood  to  a  less  mature  histological  type, 
iSTics.  such  as  that  found  in  the  blood  of  the  fetus. 
Thus,  in  children,  anemia  of  a  type  which  in  the 
adult  is  unattended  by  qualitative  changes  in  the  corpuscles  is 
commonly  associated  with  the  presence  of  large  numbers  of 
nucleated  erythrocytes,  these  cells  being  far  more  numerous  than 
the  severity  of  the  anemia  would  seem  to  warrant ;  poikilocytosis, 
and  deformities  in  the  size  of  the  corpuscles  also  occur  with  far 
greater  frequency  than  in  the  adult.  Regeneration  of  the  blood 
takes  place  slowly.  The  oligochromemia  is  relatively  greater  than 
the  oligocythemia  in  most  anemias  of  children,  this  being  due 
probably  to  the  fact  that  the  hemoglobin  is  peculiarly  prone  to 
separate  from  the  corpuscular  stroma.  Owing  to  this  fact  low 
color  indices,  as  in  chlorosis,  are  common,  irrespective  of  the 
degree  of  corpuscular  diminution. 

Myelocytes  are  commonly  found  in  the  blood  in  all  the  anemias 
of  children  ;  they  are  present  in  larger  relative  percentages  and  in 
less  severe  pathological  conditions  than  in  the  adult. 

Leucocytosis,  often  lymphocytosis,  and  enlargement  of  the  spleen 
are  frequently  associated  with  all  forms  of  anemia  in  the  young  ; 
and  although  these  conditions  are  likely  to  coexist,  this  is  by  no 
means  the  invariable  rule.  Splenic  enlargement  is  especially 
common  in  the  anemias  due  to  syphilis,  rachitis,  tuberculosis, 
gastro-intestinal  disease,  malaria,  and  septic  infection. 

To  epitomize,  in  the  anemias  of  infancy  and  childhood  the  follow- 
ing prominent  features  in  the  blood  are  found :  (a)  the  frequency 
of  a  low  color  index ;  (d)  the  common  occurrence  of  erythro- 
blasts,  and  of  deformities  affecting  the  shape  and  size  of  the 
erythrocytes ;  (c)  a  tendency  toward  leucocytosis  and  splenic 
enlargement,  and  (d)  the  frequency  of  myelocytes. 

It  is  owing  to  these  peculiarities  that  the  clas- 

Classifica-     sification  of  the  anemias  of  children  is  such  a  dif- 
TiON.  ficult   matter.     The   older  classifications,   based 

upon  the  nature  of  the  causal  factors  of  the  an- 
emia and  upon  the  presence  or  absence  of  enlargement  of  the 


284  THE    ANEMIAS    OF    INFANCY    AND    CHILDHOOD. 

Spleen,  have  failed  in  many  respects  to  prove  adequate,  so  that  it 
becomes  necessary  to  adopt  a  simpler  and  more  comprehensive 
division  from  which  no  exceptions  need  be  made  in  the  individual 
case.  Such  a  classification  has  recently  been  suggested  by 
Morse. ^  This  author  assuming,  and  rightly  so,  that  chlorosis  is 
a  condition  wholly  foreign  to  infantile  life,  and  that  the  disease  de- 
scribed by  von  Jaksch  as  "Anemia  infantum  pseudoleukemica  " 
does  not  represent  a  distinct  clinical  entity,  proposes  this  excellent 
classification,  slightly  modified  from  that  of  Monti  : 

Primary  Anemia.         Pernicious  anemia. 

Leukemia. 

Secondary  Anemia.     Mild  anemia. 

Mild  anemia  with  leucocylosis. 

Severe  anemia. 

Severe  anemia  with  leucocytosis. 

Pernicious  anemia  is  rare  in  the  young,  and 
Primary  likely  to  be  mistaken  for  other  forms  of  severe  an- 
Anemia.  emia  secondar}-  to  various  conditions.  It  is  prob- 
able that  many  of  the  reported  cases  of  Biermer's 
anemia  in  infants  were  in  reality  examples  of  severe  secondary- 
anemia.  The  apparent  tendency  of  pernicious  anemia  in  children 
to  become  transformed  into  leukemia  is  doubtless  more  fanciful 
than  real,  a  remark  which  is  equally  true  of  those  few  reported 
instances  of  the  conversion  of  leukemia  into  pernicious  anemia. 
In  the  first  case,  the  erroneous  impression  may  arise  from  such 
evidence  as  marked  enlargement  of  the  spleen  associated  with  a 
high  leucocytosis  ;  in  the  second,  a  temporary'  disappearance  of 
the  myelogenous  blood-picture  plus  an  aggravation  of  the  exist- 
ing anemia  may  be  sufficient  to  convey  the  false  impression.  It 
must  be  admitted  that  these  atypical  blood  changes,  so  common 
in  young  children,  are  highly  confusing  and  difficult  to  interpret 
without  the  closest  observation  and  the  correlation  of  other  clin- 
ical signs. 

Infantile  pernicious  anemia  is  characterized  by  the  same  blood 
changes  that  are  found  in  the  adult,  in  so  far  as  striking  oligocy- 
themia, and  nucleation  and  deformities  of  the  er}^throcytes  are 
concerned,  but  the  blood  often  fails  to  show  the  high  color 
index  and  the  prevalence  of  megaloblasts  and  of  megaloCytes 
which  must  be  considered  diagnostic  of  this  disease  in  the  adult. 

Leukemia  in  children  is  uncommon,  but  instances  have  been 
reported  during  all  stages  of  infancy  and  childhood,  even  in  the 

1  Archives  of  Pediatrics,  1898,  vol.  xv.,  p.  815. 


PRIMARY    ANEMIA.  285 

new-born.  Acute  forms  of  the  disease  are  most  frequently  met 
with,  the  great  majority  of  cases,  according  to  Holt,^  proving 
fatal  within  a  year  from  the  appearance  of  the  first  symptoms, 
while  in  many  the  disease  runs  its  course  in  a  few  weeks.  Male 
children  are  more  commonly  leukemic  than  females.  Conditions 
such  as  rachitis,  syphilis,  and  malarial  fever  have  been  regarded  by 
some  authors  as  possessing  a  certain  amount  of  importance  as 
etiological  factors,  but  in  the  vast  majority  of  cases  the  cause  of 
the  disease  is  entirely  obscure. 

Of  the  several  collected  reports  of  leukemia  in  children,  the 
two  articles  of  Morse,  giving  a  total  of  27  cases,  are  by  far  the 
most  valuable.  In  his  first  communication^  20  cases  were  re- 
corded, including  one  of  his  own,  tabulated  below,  but  of  this 
series  the  diagnosis  in  the  great  majority  of  instances  being  based 
either  upon  clinical  symptoms  or  upon  inadequate  examination 
of  the  blood,  the  reporter  is  led  to  remark  that  **  It  is  highly 
probable  that  not  more  than  half,  perhaps  not  more  than  a  third 
of  these  were  really  cases  of  leukemia."  In  Morse's  second 
article,^  which  deals  with  the  acute  form  of  the  disease,  seven 
cases,  again  including  one  of  his  own,  also  recorded  below,  are 
reported. 

Although  the  literature  of  pediatrics  is  fairly  rich  in  alleged 
examples  of  leukemia  in  children,  the  cases,  with  but  a  few  ex- 
ceptions, are  reported  in  such  an  unsatisfactory  manner  that  they 
cannot  be  regarded  without  reserve  as  typical.  Those  reported 
prior  to  the  pubHcation  of  Morse's  first  article,  in  1894,  must  all 
be  open  to  criticism,  owing  to  the  general  disregard  for  differen- 
tial counts  shown  by  the  various  authors,  and,  strangely  enough, 
this  criticism  must  hold  true  for  many  cases  recorded  during  the 
past  seven  years.  The  author  has  been  able  to  collect  ten  cases 
(Table  XIII.),  in  all  of  which  the  differential  count  of  leucocytes 
leaves  no  doubt  as  to  the  precise  character  of  the  disease. 

In  addition  to  the  above  cases  several  others  have  been  reported, 
in  which  the  differential  count  of  leucocytes  has  either  been  faultily 
made  or  entirely  neglected.  Thus,  Pollman*  believes  that  he  has 
seen  a  case  of  spleno-medullary  leukemia  in  a  new-born  infant, 
the  count  on  the  fourteenth  day  after  birth  being  2,500,000  ery- 
throcytes and  312,500  leucocytes  per  cubic  millimeter.  The 
latter  consisted  chiefly  of  ''  large  mononucleated  cells,  with  large, 
distinct  nuclei,  and  an  abundance  of  protoplasm."  Nucleated 
forms  of  erythrocytes  were  not  found.     Cassel,^  in  addition  to 

1  "The  Diseases  of  Infancy  and  Childhood,"  N.  Y.,  1897,  p.  806. 

2  Boston  Med.  &  Surg.  Journ.,  1894,  vol.  cxxxi.,  p.  133. 

3  Archives  of  Pediatrics,  1898,  vol.  xv.,  p.  330. 
*  Miinch.  med.  Woch.,  1898,  vol.  xlv.,  p.  44. 
^Berl.  klin.  Woch.,  1898,  vol.  xxxv.,  p.  76. 


286 


THE    ANEMIAS    OF    INFANXY    AND    CHILDHOOD. 


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SECONDARY    ANEMIA.  28/ 

his  own  case,  tabulated  above,  has  collected  four  other  cases  oc- 
curring in  children  under  fourteen  years  of  age. 

Theodor^  has  collected  from  German  literature  six  cases  of  acute 
leukemia  in  children  between  the  ages  of  two-and-one-half  and 
eight  years  of  age,  and  also  reports  one  of  his  own,  apparently 
of  the  lymphatic  form,  in  a  boy  of  four  years.  No  actual  numer- 
ical estimates  of  the  corpuscles  are  given,  but  the  proportion  of 
leucocytes  to  erythrocytes  is  stated  to  vary  from  i  :  9  to  1:3. 
The  differential  count  of  leucocytes  is  also  very  inexact.  The 
greater  percentage  apparently  consisted  of  lymphocytes  ;  myelo- 
cytes were  fairly  numerous,  many  of  them  containing  mitotic  fig- 
ures, and  normoblasts  and  megaloblasts  were  present  in  large 
numbers.  Charon  and  Gratea^  report  a  case  of  spleno-medul- 
lary  leukemia  in  a  child  of  eight  years,  the  percentage  of  hemo- 
globin being  39,  the  erythrocyte  count  880,000,  and  the  leuco- 
cyte count  305,000. 

In  the  above  classification  of   the   secondary 

Secondary      anemias,  under  the  heading  of  mild  anemia  are 
Anemia.        included  those  cases  characterized  by  trifling  re- 
duction in  the  hemoglobin  percentage  and  num- 
ber of  erythrocytes,  and  by  an  absence  of  histological  alterations 
in  these  cells.     The  color  index  in  these  cases  is  usually  i  .00,  or 
slightly  below,  uncommonly  falling  to  a  low  figure. 

The  term  severe  anemia  includes  cases  having  marked  diminu- 
tion of  hemoglobin  and  erythrocytes,  associated  with  deformities 
of  shape  and  of  size  and  nucleation  of  these  cells.  The  hemo- 
globin loss  is  especially  marked,  often  being  only  one-quarter  or 
one-third  of  normal,  and  the  color  index  is  low. 

Anemias  with  lencocytosis^  whether  of  mild  or  of  severe  type, 
are  generally  marked  by  a  greater  degree  of  hemoglobin  and 
corpuscular  decrease  than  anemias  without  leucocytosis.  The 
leucocytosis  is  moderate  in  the  milder  forms,  but  in  severe  cases 
the  increase  in  the  number  of  leucocytes  often  appears  to  be  pro- 
gressive, and  the  relative  number  of  leucocytes  to  erythrocytes 
occasionally  attains  the  proportion  i  to  100. 

Histological  changes  in  the  erythrocytes  are  more  striking  in 
grave  anemias  with  leucocytosis  than  in  grave  anemias  pure  and 
simple.  This  is  especially  true  of  the  changes  relating  to  nuclea- 
tion of  the  cells,  normoblasts  and  atypical  forms  being  very  nu- 
merous in  the  former  class.  Typical  megaloblasts  are  occasion- 
ally found,  but  these  cells  are  not  common  in  the  blood  of  chil- 
dren, even  in  the  most  severe  anemias. 

^Archiv.  f.  Kinderheilk. ,  1897,  vol.  xxii,,  p.  47. 

2 Bull.  Soc.  roy.  sc.  med.  et  nat.,  Bruxelles,  1896,  vol.  liv.,  p.  63. 


288  THE    ANEMIAS    OF    INFANCY    AND    CHILDHOOD. 

Regarding  the  etiological  factors  of  these  secondary  anemias, 
the  following  groups  of  causes  are  given  by  Monti  -} 

I.  Congenital.  |  Syphilis,  tuberculosis,  and  other  infections. 


Hemorrhagic. 


2.  Acquired. 

General. 


From  navel,  from  circumcision,  etc. 
Purpuric  diseases. 

Malnutrition,  improper  hygiene,  etc. 
Syphilis,  rachitis,  and  tuberculosis. 
Gastro-intestinal  diseases. 
Visceral  diseases. 
Febrile  diseases. 
Septic  infections. 
Nephritides. 
Malignant  growths. 

Syphilis,  either  congenital  or  acquired,  is  responsible  for  a  large 
proportion  of  the  cases  of  anemia  in  children,  especially  those  of  a 
severe  type,  associated  with  enlargement  of  the  spleen,  and  often 
also  with  enlargement  of  the  lymphatic  glands.  The  hemoglo- 
bin loss  is  in  most  instances  disproportionately  greater  than  the 
corpuscular  decrease,  so  that  low  color  indices  are  especially 
common  in  this  disease — the  misnamed  **  chlorosis  "  of  syphilis. 
Deformities  and  nucleation  of  the  er}lhrocytes  are  common 
in  the  severer  types,  and  in  such  forms  polychromatophilic 
changes  and  excessive  decrease  in  the  number  of  er^^throcytes 
are  usually  present.  A  leucocyte  increase  is  present  in  the  sec- 
ondary stage,  and  is  usually  associated  with  the  grave  anemia 
of  this  disease  ;  the  relative  precentage  of  lymphocytes  is  in- 
creased, and  of  polymorphous  forms  decreased  ;  and  small  num- 
bers of  myelocytes  are  common.  From  the  writer's  experience, 
in  the  average  case  of  moderate  severity  the  percentage  of  hemo- 
globin varies  from  about  40  to  50,  the  erythrocytes  are  reduced 
to  about  3,000,000  to  3,500,000  per  cubic  millimeter,  and  the 
leucocyte  count  is  in  the  neighborhood  of  20,000  ;  but  in  severe 
cases  the  erythrocytes  may  be  reduced  to  1, 000,000,  and  the  leu- 
cocytes increased  to  50,000  or  more.  As  in  the  adult,  Justus' 
test  proves  of  value  in  the  diagnosis  of  many  anomalous  cases. 

In  rachitis  there  is  usually  well-marked  anemia,  commonly 
accompanied  by  decided  enlargement  of  the  spleen,  such  cases 
usually  having  most  decided  blood  changes.  The  hemoglobin 
percentage  is  usually  relatively  lower  than  the  percentage  of 
corpuscles,  so  that  low  color  indices  prevail ;  but  in  the  indi- 
vidual case  neither  the  oligochromemia  nor  the  oligocythemia 
are  usually  as  marked  as  in  syphilis.  In  severe  cases,  deformed 
and  nucleated  erythrocytes,  and  a  small  percentage  of  myelo- 
cytes are  commonly  found.     The  number  of  leucocytes  is  as  a 

^  Wien.  med.  Woch.,  1894,  vol.  xliv. ,  pp.  401,  464,  516,  560,  and  613. 


SECONDARY    ANEMIA.  289 

rule   moderately  increased,  and   relatively   high   percentages  of 
lymphocytes  are  common. 

Uncomplicated  tuberculosis,  due  to  pure  infections  with  the 
tubercle  bacillus,  produces  an  anemia  which  varies  in  degree 
with  the  severity  of  the  constitutional  effects  of  the  disease.  The 
hemoglobin  and  erythrocytes  are  usually  but  slightly  decreased, 
the  former  suffering  a  relatively  greater  loss,  and  the  number  of 
leucocytes  does  not  rise  above  normal.  If  to  the  tuberculous 
process  a  septic  infection  is  superadded,  the  anemia  becomes 
severer,  and  leucocytosis,  involving  the  polymorphous  forms  of 
leucocytes,  occurs.  Splenic  enlargement  is  common,  and  some- 
times marked.  The  anemia  of  tuberculosis  is  in  no  way  referable 
to  the  infection  itself,  but  depends  upon  the  drain  on  the  albumi- 
noid materials  of  the  blood  due  to  the  presence  of  a  long-con- 
tinued cachexia. 

G astro-intestinal  diseases,  especially  those  of  chronic  character, 
cause  most  marked  anemia.  Chronic  inflammations  of  the  intes- 
tines strikingly  affect  the  blood,  the  percentage  of  hemoglobin 
frequently  falling  to  one-quarter  of  normal  or  even  less,  and  the 
number  of  erythrocytes  being  decreased  to  one-half  of  normal  or 
less.  Deformities  affecting  the  shape  and  size  of  the  erythrocytes, 
and  nucleation  of  these  cells  are  of  frequent  occurrence.  A  leu- 
cocyte increase,  involving  in  many  instances  the  lymphocytes, 
is  usually  present,  and  small  percentages  of  myelocytes  have 
been  observed.  Splenic  enlargement  is  frequently  a  'conspicu- 
ous clinical  sign.  It  should  be  remembered  that  in  acute  forms 
of  gastro-intestinal  disorders,  in  which  profuse  diarrhea  and  vom- 
iting occur,  concentration  of  the  blood  takes  place,  causing  tem- 
porary polycythemia  which  may  for  a  time  hide  the  real  degree 
of  the  blood  deterioration.  The  anemias  found  in  this  class  of 
diseases  are  apparently  to  a  large  extent  autointoxicative  in  char- 
acter, depending  to  a  less  degree  upon  insufficient  nutrition. 

In  enteric  fever  the  blood-picture  does  not  differ  essentially 
from  that  seen  in  the  adult  suffering  from  this  affection,  absence 
of  leucocytosis  or  leucopenia  with  progressive  anemia  being 
found  with  great  constancy.  In  12  cases  recently  studied  by 
Stengel  and  White  ^  the  hemoglobin  ranged  from  68  to  83  per 
cent.,  the  erythrocytes  from  3,320,000  to  5,200,000,  and  the  leu- 
cocytes (in  uncomplicated  cases)  from  3,800  to  12,320.  Poly- 
nuclear  leucocytosis  was  obsei'ved  in  3  cases  as  the  result  of  in- 
flammatory complications.  Two  uncomplicated  cases  showed 
fractional  percentages  of  myelocytes,  but  there  were  no  other  dif- 
ferential changes  of  any  consequence.     The  writer  has  found  that 

^Archives  of  Pediatrics,  1901,  vol.  xviii.,  pp.  241  and  321. 
19 


290  THE    ANEMIAS    OF    INFANCY    AND    CHILDHOOD. 

the  alkalinity  of  the  blood  varies  within  wide  limits  in  infantile 
typhoid,  tests,  by  Engel's  method,  in  6  consecutive  cases  showing 
a  range  of  from  373  to  692  mgrms.  NaOH.  The  rapidity  of  co- 
agulation also  was  found  to  vary  greatly,  clotting  taking  place  in 
as  short  a  time  as  37  seconds  in  one  instance,  and  not  occurring 
for  4  minutes  and  35  seconds  in  another.  Morse  ^  concludes  that 
the  serum  test  appears  earlier,  is  less  marked,  and  persists  for  a 
shorter  period  in  children  than  in  adults.  In  a  nursling  it  should 
be  remembered  that  a  positive  reaction  may  be  of  uncertain  value, 
for  the  reason  that  the  agglutinating  power  may  be  transmitted 
from  mother  to  child  through  the  milk,  both  during  the  active 
stages  of  the  disease  and  also  during  and  after  convalescence. 

Under  the  title  ''Anemia  infantum  psctidolctikemica^  von 
Jaksch  ^  has  described  a  condition  which  he  regards  as  a  form  of 
primary  anemia  peculiar  to  the  young  child.  The  blood  changes, 
none  of  which  are  characteristic  of  the  disease  in  question,  as  this 
author  admits,  consist  of  {a)  marked  oligocythemia  and  oligo- 
chromemia,  {U)  extensive  and  persistent  leucocyte  increase,  and 
{c)  striking  structural  alterations  in  the  erythrocytes.  Associated 
with  these  changes  in  the  blood,  and  of  equal  importance  in  diag- 
nosing the  disease,  constant  enlargement  of  the  spleen,  and,  less 
commonly,  enlargement  of  the  liver  are  found. 

The  number  of  erythrocytes  is  greatly  decreased,  usually  to 
from  2,000,000  to  3,000,000  per  cubic  millimeter,  but  sometimes 
falling  to  1 ,000,000  or  even  to  a  lower  figure,  as  in  one  of  von 
Jaksch's  cases,  in  which  the  count  was  only  820,000.  The 
hemoglobin  loss  is  also  great,  relatively  more  so  than  the  cor- 
puscular decrease. 

The  leucocyte  gain  is  decided,  averaging,  in  the  majority  of 
cases,  from  30,000  to  50,000  corpuscles  per  cubic  millimeter,  and 
in  some  instances  exceeding  100,000.  In  some  cases  the  in- 
crease involves  principally  the  polynuclear  neutrophiles,  while 
in  others  the  lymphocytes  are  the  cells  chiefly  affected.  The 
cells  show  a  most  striking  dissimilarity  of  form  and  of  size,  and 
a  highly  confusing  variety  of  forms  atypical  in  size,  shape,  and  nu- 
clear morphology  is  encountered.  This  ** polymorphous"  state 
of  the  leucocytes  is  a  point  insisted  upon  by  von  Jaksch  in  his 
description  of  the  condition.  The  number  of  eosinophiles  varies 
within  wide  limits,  the  percentage  of  these  cells  being  normal, 
decreased,  or  increased.  Small  percentages  of  myelocytes  have 
been  observed. 

The  histological  changes  affecting  the  erythrocytes  consist  in 

'Archives  of  Pediatrics,  1901,  vol.  xviii.,  p.  338. 
2Wien.  klin.  Woch.,  1889,  vol.  ii.,  p.  435. 


SECONDARY    ANEMIA.  29 1 

marked. poikilocytosis,  deformities  of  size,  loss  of  color,  and  nu- 
cleation.  Poikilocytes,  megalocytes,  and  microcytes  occur  in 
large  numbers,  and  the  pallor  of  most  of  the  corpuscles  is  ex- 
treme. Normoblasts  are  the  most  common  form  of  erythro- 
blasts  observed,  but  in  some  instances  the  occurrence  of  atypical 
forms,  small  and  large,  and  of  megaloblasts  has  been  noted. 
Karyokinetic  changes  in  these  cells  are  not  uncommonly  seen, 
and  polychromatophilia  is  said  to  be  of  frequent  occurrence. 

The  spleen  is  enlarged  in  all  cases,  sometimes  moderately,  but 
often  very  greatly,  so  that  the  organ  extends  far  below  the  cos- 
tal margin,  and  occupies  the  entire  upper  left  part  of  the  abdomi- 
nal cavity.  The  spleen  is  extremely  indurated,  and  may  show 
capsular  thickening  from  perisplenitis.  The  increase  in  the  size 
of  the  organ  is  due  to  a  hyperplasia.  Increase  in  the  size  of  the 
liver  is  not  constant  in  all  cases,  and  when  present  does  not 
reach  a  size  corresponding  to  that  of  the  spleen,  as  is  the  case  in 
leukemia ;  the  lower  border  of  the  liver  is  not  rounded,  but  dis- 
tinctly sharp.  In  a  certain  proportion  of  cases  the  lymphatic 
glands  are  slightly  enlarged,  but  never  to  any  notable  extent. 
Changes  in  the  bone  marrow,  common  to  any  severe  anemia, 
have  been  observed  in  some  cases. 

The  disease  occurs  most  frequently  in  infants  between  the  ages 
of  seven  and  twelve  months,  and  is  rarely  met  with  in  children 
over  four  years  old.  By  some  writers  it  is  supposed  to  be  slightly 
more  common  in  children  of  the  male  sex. 

In  many  cases  a  previous  history  of  rachitis,  syphilis,  or  long- 
standing gastro-intestinal  disease  is  obtained,  although  von  Jaksch 
denies  the  existence  of  these  etiological  factors  in  his  cases. 

The  onset  of  the  symptoms  is  slow  and  insidious,  and  the  pal- 
lor of  the  skin,  blanching  of  the  mucous  membranes,  and  other 
signs  of  anemia  slowly  develop,  with  the  gradual  enlargement  of 
the  spleen,  until  these  clinical  manifestations  become  marked. 
In  all  cases  there  is  excessive  loss  of  strength,  and  in  a  great 
many  a  high  degree  of  emaciation. 

Von  Jaksch's  disease,  if  untreated,  tends  to  pursue  a  progres- 
sively grave  course,  ending  fatally  ;  but,  under  suitable  treat- 
ment, in  the  majority  of  cases  the  splenic  tumor  decreases  in 
size,  the  leucocytosis  disappears,  and  the  hemoglobin  and  eryth- 
rocytes return  to  normal. 

Pseudoleukemic  anemia  of  infants  is  not  generally  considered 
as  a  separate  clinical  entity,  but  is  regarded  rather  as  a  form  of 
severe  secondary  anemia  associated  with  marked  leucocytosis  and 
splenic  enlargement.  It  may  be  due  -to  a  number  of  different 
causes,  the  most  prominent  among  which  are  syphilis,  rachitis. 


292  THE    ANEMIAS    OF    INFANCY    AND    CHILDHOOD, 

and  chronic  gastro-intestinal  disease.  The  conflicting  reports  of 
different  authors  concerning  this  disease,  and  the  incompleteness 
with  which  the  leucocytes  hav^e  been  studied  in  many  instances, 
render  it  probable  that  in  some  of  the  reported  cases  pernicious 
anemia  and  leukemia  have  masqueraded  as  typical  examples  of 
the  condition  described  by  von  Jaksch. 

Bacterionia,  generally  referable  to  pre-agonal  infections,  appears 
to  occur  with  great  frequency  in  the  young  child  during  the  course 
of  many  acute  diseases.  Delestre's  recent  studies^  of  general 
blood  infections  in  children  tend  to  show  that  infants  born  before 
full  term  are  peculiarly  susceptible  to  this  condition.  Using  care- 
ful technique,  this  author  examined  40  children,  ranging  in  age 
from  a  few  days  to  four  }-ears,  all  of  whom  were  believed  to  be 
suffering  from  infections  which  bade  fair  to  end  fatally  within  a 
few  days,  at  the  latest.  Of  the  32  fatal  cases  of  this  series,  bacteria 
were  found  in  the  blood  during  hfe  in  14,  while  of  the  8  who  re- 
covered, but  one  gave  a  positive  result.  The  bacterium  found 
with  greatest  frequency  was  the  streptococcus,  while  staphylococci, 
pneumococci,  colon  bacilli,  and  influenza  bacilli  were  isolated  more 
rarely.  It  was  furthermore  shown  that  premature  babies  seemed 
especially  susceptible  to  streptococcus  and  colon  infections,  and 
that  nursing  infants  sev^eral  months  old  were  more  prone  to  suffer 
from  the  effects  of  the  staphylococcus. 

The  blood  changes  occurring  '\\\  pertussis,  pneumonia,  diphtheria, 
scarlet  fever,  measles,  and  other  infectious  diseases  of  childhood 
are  considered  in  Section  VII. 

1  Annal.  degynecol.  etd'obstet.,  1901,  vol.  Iv.,  p.  51. 


SECTION   VII. 


GENERAL    HEMATOLOGY. 


SECTION    VII. 
GENERAL    HEMATOLOGY. 


I.    ABSCESS. 


The  rate  oi  coagulation  is,  as  a  rule,  somewhat 
General      slower  than  normal.     Hyperinosis  is  conspicuous, 
Features,     and  under  the  microscope  the  fibrin  network  ap- 
pears  abnormally  dense  and   thick.     The  iodine 
reaction  may  be  detected  in  the  dried  blood  film  by  the  method 
described  in  a  previous  section.     (See  page  174.)    These  remarks, 
as  well  as  those  which  follow,  do  not  apply  to  purely  tuberculous  or 
*'  cold"  abscesses,  the  effects  of  which  are  referred  to  elsewhere. 
If  the  absorption  of  toxic  material  from  an  ab- 
Hemoglobin    scess  is  great  enough  to  produce  a  systemic  effect 
AND  upon  the  patient,  anemia  of  an  intensity  parallel 

Erythrocytes,  to  the  severity  of  the  poisoning  sooner  or  later 
develops.  This  fact  is  sufficient  to  explain  why 
the  grades  of  anemia  in  purulent  conditions  vary  within  such  wide 
limits.  The  size  and  the  site  of  the  abscess  do  not  appear  pri- 
marily to  determine  the  degree  of  the  associated  blood  changes, 
although,  other  circumstances  being  equal,  a  large,  deep-seated 
collection  of  pus  is  likely  to  have  a  more  harmful  effect  than  one 
of  small  size  and  superficial  situation.  Chronicity  of  the  lesion 
seems  to  go  hand  in  hand  with  an  increase  in  the  blood  deterio- 
ration— few  persons  harboring  pus  for  a  protracted  period  fail  to 
show  decided  signs  of  anemia. 

In  many  cases,  especially  the  acute,  the  only  noticeable  change 
is  a  moderate  oligochromemia,  but  in  chronic  cases  different  de- 
grees of  ordinary  secondary  anemia  are  commonly  encountered, 
amounting  in  an  exceptional  instance  to  a  reduction  of  hemo- 
globin to  as  low  as  20  or  30  per  cent,  of  the  normal  standard,  and 
to  an  erythrocyte  decrease  to  between  2,000,000  and  3,000,000 
cells  to  the  cubic  miUimeter.  Such  profound  losses  are  of  course 
unusual,  for  in  the  majority  of  patients  with  anemia  the  hemo- 
globin is  above  50,  and  the  corpuscles  above  60  per  cent,  of  nor- 
mal. The  average  color  index  for  76  German  Hospital  cases, 
Hsted  below,  was  0.73.  The  condition  of  the  hemoglobin  and 
erythrocytes  in  these  patients  is  shown  by  the  following  summary : 


296 


GENERAL    HEMATOLOGY. 


/.  Superficial  abscess  of 
hand,  arm,  foot,  and  abdout- 
inal  wall ;  pahnar,  axillary, 
cerzncal,  cerebral,  hepatic, 
renal,  periurethral,  and 
ischio-rectal  abscess;  empyema 
of  gall-bladder . 


II.  Pelvic   abscess:   o7>ar- 
ian  abscess  :  pyosalpinx. 


UOGLOBI 

IN  Percentage. 

N 

10. 

OF  Cases. 

Nc 

1.  OF   Cases. 

From 

90 

to 

100 

I 

0 

80 

to 

90 

3 

I 

70 

to 

80 

7 

5 

60 

to 

70 

7 

4 

50 

to 

60 

6 

9 

40 

to 

50 

10 

9 

30 

to 

40 

5 

3 

20 

to 

30 

3 

3 

Average : 

57- 

,0 

per  cent. 

54 

.0 

per  cent. 

Maximum  : 

95- 

0 

(( 

82, 

.0 

(( 

Minimum : 

20. 

0 

( ( 

22. 

,0 

( ( 

Erythrocytes  per  cb.  mm. 

Above  5,000,000  5 

From  4,000,000  to  5,000,000  14 

**     3,000,000  to  4,000,000  18 

'■'■     2,000,000  to  3,000,000  3 

*'     1,000,000  to  2,000,000  2 

.\verage  :  3,881,190  per  cb.  mm. 

Maximum:           5,250,000    "  *' 

Minimum  :           1,500,000    ''  '' 


o 

12 
18 

3 

I 


3,634,823  per  cb.  mm. 
4,730,000    '' 
1,310,000    ''        " 


If  marked  anemia  exists,  a  variable  grade  of  cell  deformit>% 

atypical  staining,  and  nucleation  is  also  to  be  obser\'ed.     If  the 

latter  change  is  evident,  it  will  be  found  that  the  great  majority,  if 

not  all, of  the  nucleated  corpuscles  belong  to  the  normoblastic  class. 

Practically  the  same  influences  governing  the 

Leucocytes,  behavior  of  the  leucocytes  in  most  other  infec- 
tions also  determine  their  increase  and  decrease 
in  abscess.  Thus,  in  both  trivial  and  in  extensive  pus  foci  the 
number  of  leucocytes  may  be  normal,  or  even  subnormal ;  in  the 
former  instance  because  systemic  reaction  is  not  provoked,  and 
in  the  latter  because  it  is  overpowered.  Leucocytosis  may  also 
be  absent  in  case  toxic  absorption  is  impossible,  owing  to  the 
complete  walling-off  of  the  abscess.  In  all  other  instances 
save  these,  a  definite  and  usually  well-marked  leucocytosis 
occurs,  amounting  on  the  average  to  a  count  of  about  twice 
the  mean    normal    standard,    but   frequently   greatly   exceeding 


ABSCESS.  297 

this  figure  in  the  individual  case.  The  size  of  the  primary 
abscess  cannot  be  estimated  by  the  height  of  the  leucocytosis, 
but  a  tendency  of  the  pus  to  extend  is  almost  always  accom- 
panied by  a  distinct  increase  in  the  number  of  cells  in  excess  of 
the  figure  originally  estimated.  Complete  evacuation  of  the  ab- 
scess is  soon  followed  by  a  disappearance  of  the  leucocytosis,  but 
so  long  as  the  pus  remains  ineffectually  drained  the  high  count 
tends  to  persist. 

The  frequency  of  leucocytosis  and  the  range  of  the  counts  in 
various  forms  of  abscess  are  shown  by  the  following  summary  of 
the  cases  already  mentioned  : 

/.  Superficial  abscess  of 
hand,  arm,  foot,  and  abdom- 
inal wall ;  pahnar ,  axillary, 
cervical,  cerebral,  hepatic, 
renal,  periurethral,  and 
ischio-rectal      abscess;       etn-       II.  Pelvic  abscess ;  ovarian 


pyema  0/ gall-bladder . 

abscess  ;  pyosalpinx. 

Leucocytes  per  c\ 

Above  35,000 
From  30,000  to 

5.    MM. 

35>ooo 

No.  OF  Cases. 
0 
0 

No. 

OF  Cases. 

3 
0 

''      25,000 

to 

30,000 

0 

I 

*'     20,000 

to 

25,000 

7 

3 

''      15,000 

to 

20,000 

9 

8 

*'      10,000 

to 

15,000 

20 

10 

*'        8,000 
**        6,000 

to 
to 

10,000 
8,000 

4 

I 

4 
4 

*'       4,000 
Below  4,000 

to 

6,000 

I 
0 

0 
I 

Average : 
Maximum 
Minimum : 

14, 
24, 

4, 

388  per  cb.  mm. 
000    '' 
800    '' 

15 
41 

,548 
,000 

per  cb.  mm. 

(I               (C 

A  polynuclear  neutrophile  gain  accounts  for  the  increase  when 
leucocytosis  is  present,  and,  rarely,  this  differential  change  may 
be  found  without  any  increase  in  the  total  number  of  leucocytes. 
A  few  myelocytes  may  occasionally  be  observed  in  cases  having 
a  decided  anemia  or  a  high  leucocytosis. 

The  presence  of  leucocytosis,  especially  if  as- 

DiAGNOSis.  sociated  with  hyperinosis  and  a  positive  iodine 
reaction,  is  suggestive  of  abscess  rather  than  of 
other  lesions,  such  as  aneiansms,  gummata,  hematomata,  and  benign 
neoplasms.  An  absence  of  one  or  all  of  these  signs,  on  the  other 
hand,  is  not  sufficient  to  exclude  pus.  The  distinctions,  as  shown 
by  the  blood,  between  pyogenic  and  tuberculous  abscesses  and 
malignant  disease  are  considered  under  the  last-named  conditions. 


298  GENERAL    HEMATOLOGY. 


II.     ACROMEGALY. 

The  following  counts  illustrate  the  blood  changes  found  in  two 
cases  of  this  disease,  the  first  showing  practically  normal  blood, 
except  for  a  moderate  relative  lymphocytosis  and  an  absence  of 
eosinophiles,  and  the  second  simply  a  well-marked  secondary 
anemia,  with  a  high  color  index. 

Case  I.  Case  IL 

Hemoglobin.  86  per  cent.  60  per  cent. 

Erythrocytes.  4,620,000  per  cb,  mm.  2,880,000  per  cb.  mm. 

Color  index.  0.93  1.04 

Leucocytes.  8,000  per  cb.  mm.  4,890  per  cb.  mm. 

Small  lymphocytes.  31.7  per  cent.  21.0  per  cent. 

Large  lymphocytes.  2.1        "  7.0 

Polynuclear  neutrophils.  66.2       "  71. o 
Eosinophiles.                                      0.0       "  I.O 

Basophiles.  .  0.0       "  0.0 

Myelocytes.  0.0       "  0.0 

The  erythrocytes  showed  moderate  deformities  of  size  and 
shape  in  the  anemic  case,  but  neither  signs  of  nucleation  nor  of 
basophilic  stroma  degeneration  were  observed.  Coagulation, 
fibrin  formation,  and  the  number  of  plaques  were  apparently 
normal. 

III.    ACTINOMYCOSIS. 

A7i€}}ua,  marked  by  a  disproportionately  great  hemoglobin  de- 
crease, is  generally  found,  and  leiicocytosis  appears  to  be  a  con- 
stant feature  of  the  blood-picture,  judging  from  the  small  number 
of  reports  available.  It  is  probable  that  the  grade  of  both  the 
anemia  and  the  leucocytosis  depends  largely  upon  the  amount 
of  septic  absorption  originating  from  the  lesion. 

IV.     ACUTE    YELLOW    ATROPHY   OF   THE    LIVER. 

Malignant  jaundice  appears  to  be  associated  with  a  moderate 
polycytJiCDiia^  so  far  as  can  be  determined  by  the  limited  number 
of  blood  counts  made  in  this  disease  up  to  the  present  time. 
The  leucocytes  are  moderately  increased  in  number,  but  show  no 
peculiar  differential  changes,  so  far  as  is  known.  In  two  cases, 
reported  by  Grawitz,'  and  by  Cabot, ^  respectively,  the  counts  of 
erythrocytes  were  5,150,000  and  5,520,000,  and  the  number  of 
leucocytes  12,000  and  16,000  per  cubic  millimeter.  Bacterio- 
logical exauiinatioii  of  the  blood  has  thrown  no  definite  light 
upon  the  nature  of  this  apparently  infectious  process.  In  many 
cases  hemoglobinemia  and  lipacidemia  have  been  detected. 

'  Loc.  cit. 


Addison's  disease.  299 

V.     ADDISON'S    DISEASE. 

Moderate  anemia  is   commonly,  and   decided 
Hemoglobin     anemia  occasionally,  associated  with  this  condi- 
and  tion,    although    the    prime    importance    of  this 

Erythrocytes,  symptom  insisted  upon  by  Addison  himself  ap- 
pears to  be  somewhat  exaggerated,  in  the  light 
of  our  more  accurate  methods  of  blood  study.  The  ''  anemiated 
eye  "  of  Addison  does  not  always  mean  anemia.  In  advanced 
cases  the  blood-picture  may  be  characterized  by  marked  hemo- 
globin and  erythrocyte  losses,  by  the  presence  of  numerous 
poikilocytes  and  microcytes,  and  by  small  numbers  of  normo- 
blasts ;  the  hemoglobin  readings  in  such  instances  range  between 
20  and  40  per  cent.,  and  the  erythrocyte  counts  between  2,000,- 
000  and  3,000,000  per  cubic  millimeter,  or  even  less.  Tschir- 
koff  ^  reports  cases  in  which,  notwithstanding  the  coexistence  of  a 
notable  oligocythemia,  the  hemoglobin  percentage  remained 
normal  or  above  normal,  and  this  pecuHar  condition  he  referred 
to  an  increase  in  the  amount  of  corpuscular  reduced  hemoglobin. 
This  author  also  detected  the  presence  of  methemoglobin  and 
melanin  in  the  blood  of  patients  suffering  from  Addison's  disease. 
The  polycythemia  which  is  sometimes  met  with  in  this  condition 
is  doubtless  to  be  attributed  to  such  factors  as  vasomotor 
changes,  and  blood  inspissation  from  emesis.  Treatment  with 
suprarenal  extract  tends  to  improve  the  anemia,  but  to  what  ex- 
tent and  how  permanently  is  undetermined. 

The  number  of  leucocytes  is  usually  normal, 
Leucocytes,  or  below  normal,  and  extreme  leucopenia  has 
been  repeatedly  noted.  Relative  lymphocytosis 
and  sometimes  a  moderate  increase  in  the  number  of  eosinophiles 
are  the  most  familiar  differential  changes,  together,  in  some  in- 
stances, with  the  presence  of  a  few  myelocytes,  and  basophilic 
leucocytes. 

VI.     ANTHRAX. 

In  the  light  of  our  present  knowledge  nothing  definite  is  known 
of  the  behavior  of  the  hemoglobin  and  corpuscles  in  this  infection. 
Only  occasionally  can  the  anthrax  bacillus  be  isolated  from  the 
peripheral  blood,  since  general  invasion  of  the  circulation  by  this 
organism  is  rare.  Blumer  and  Young ^  succeeded  in  finding  the 
organism  in  the  blood  of  a  single  case  of  anthrax  septicemia,  both 
in  ordinary  cover-glass  specimens,  as  well  as  by  culturing. 

^  Zeitschr.  f.  klin.  Med.,  1890,  vol.  xix.,  p,  87. 

2  Johns  Hopkins  Hosp.  Bull.,  1895,  vol.  vi,,  p.  127. 


iOO 


GENERAL    HEMATOLOGY. 


VII.     APPENDICITIS. 

Fully  three-fourths  of  all  cases  of  appendicitis. 
Hemoglobin    whatever  their  character,  show  a  loss  of  at  least 
AND  30  per  cent,  of  hemoglobin,  while  in  about  one 

Erythrocytes,  case  in  five  the  er>'throcytesare  diminished  1,000,- 
000  or  more  to  the  cubic  millimeter.  From  an 
analysis  of  the  cases  tabulated  below,  it  appears  that  the  average 
hemoglobin  loss  amounts  to  about  25  per  cent.,  and  the  average 
decrease  in  er>'throcytes  to  about  1 5  per  cent,  of  the  normal 
standard.  The  anemia,  which  may  usually  be  attributed  to  the 
effects  of  septicemia,  is  most  frequent  and  most  marked  in  long- 
standing cases  of  appendicular  abscess,  in  which  type  of  the  dis- 
ease the  hemoglobin  may  fall  to  between  30  and  40  per  cent., 
and  the  corpuscles  to  between  2,000,000  and  3,000,000  per  cubic 
millimeter.  In  such  instances  the  risk,  actual  or  reputed,  of 
operating  upon  a  patient  having  such  a  low  percentage  of  hemo- 
globin must  be  recalled  by  the  surgeon.  Anemia,  usually  of  a 
more  moderate  grade,  is  also  frequently  found  in  catarrhal  cases, 
and  in  the  individual  instance  it  may  reach  as  high  a  grade  as  in 
the  purulent  form  of  the  disease.  The  blood  impoverishment 
in  such  instances  depends  probably  upon  the  debilitated  state  of 
the  patient,  apart  from  the  appendix  inflammation. 

The  following  table  illustrates  the  range  of  the  hemoglobin  and 
erythrocytes,  as  shown  by  the  initial  examinations  of  139  cases  in 
Dr.  J.  B.  Deaver's  wards  at  the  German  Hospital  : 


Number  of  Cases. 


Hemoglobin  Percentage. 
Above   IOO 

From  90  to  100 

"  80  to  90 

"  70  to  80 

'*  60  to  70 

"  50  to  60 

"  40  to  50 

**  30  to  40 

Highest : 
Lowest : 
Average  : 


Non-purulent. 

I 
I 

9 
13 

13 

6 

2 
o 

102  per  cent. 

45        " 
69.5     - 


Erythrocytes  per  cb.  mm. 

.•\bove  5,000,000  6 

From  4,000,000  to  5,000,000  27 

*'       3,000,000  to  4,000,000  II 

"     2,000,000  to  3,000,000  I 


Purulent,  Perforative,  and 
Gangrenous. 

O 

4 
20 

31 
23 

7 
6 


TOO  per  cent. 

38    " 

72.5  " 

14 
60 

15 
5 


APPENDICITIS.  301 

Highest:  5,660,000  per  cb.  mm.    5,710,000  per  cb.  mm. 

Lowest:  2,050,000    "  "  2,100,000    '^         ^' 

Average:  4,295,955    "         *'         4,381,234    " 

Qualitative  changes  in  the  erythrocytes  are  neither  common 
nor  important,  occurring  only  in  cases  with  decided  anemia,  and 
consisting  simply  in  deformities  of  shape  and  of  size.  Eiythro- 
blasts  apparently  do  not  occur,  although  there  is  no  reason  why 
they  should  not,  if  the  anemia  happens  to  be  of  a  type  of  sufficient 
severity  to  provoke  marrow  changes. 

In  simple  appendicular  inflammation,  uncompli- 
Leucocytes.  cated  by  pus,  gangrene,  or  peritonitis,  there  is  as  a 
rule  little  or  no  increase  in  the  number  of  leuco- 
cytes, although  in  an  exceptional  case  the  leucocytosis  is  fairly 
well  defined.  Thus,  of  the  45  cases  of  this  form  of  the  disease,  be- 
low referred  to,  less  than  9  per  cent,  were  accompanied  by  a  count 
in  excess  of  15,000,  the  maximum  estimate  being  17,100,  and  the 
average,  8,987  per  cubic  miUimeter.  A  relatively  high  count  in 
this  variety  of  appendicitis  may  usually  be  attributed  to  a  limited 
periappendicular  peritonitis.  In  some  instances  it  is  possible  that 
the  increase  may  be  due  to  blood  inspissation  from  vomiting  and 
purging,  or  that  it  may  simply  represent  a  blood  finding  of  the 
associated  anemia. 

In  cases  with  abscess,  gangrene,  or  general  peritonitis  a  well- 
marked  leucocytosis  is  the  general  rule.  Few  cases  of  appen- 
dicular abscess  fail  to  increase  the  leucocyte  count  to  at  least 
15,000  or  20,000  to  the  cubic  millimeter,  although  it  is  to  be 
remembered  that  should  the  purulent  focus  happen  to  be  so 
effectually  walled  off  that  absorption  of  toxic  material  is  prac- 
tically prevented,  such  a  decided  increase  does  not  develop.  A 
trivial  increase,  or,  indeed,  an  absence  of  leucocytosis  is  also  met 
with  in  an  occasional  grave  case  (such,  for  instance,  as  one  com- 
plicated by  a  general  purulent  peritonitis),  owing  to  the  prostra- 
tion of  the  patient  from  the  systemic  poison  of  the  infection.  As 
shown  below,  the  average  count  in  purulent  and  gangrenous  ap- 
pendicitis is  higher  than  the  maximum  count  in  the  catarrhal  form 
of  the  affection. 

A  high  leucocytosis  suggests  either  a  localized  abscess  or  a 
general  peritonitis,  for  the  differentiation  of  which  other  clinical 
data  are  absolutely  essential.  The  belief  is  current  that  if  a 
marked  leucocytosis  occurs  early  in  the  attack  peritonitis  is  prob- 
able, and  if  it  occurs  after  the  first  week  a  local  accumulation  of  pus 
is  suggested.  While  this  is  undoubtedly  true  in  many  instances, 
in  many  others  the  condition  of  the  appendicular  lesion  may  be 
wrongly  interpreted,  if  too  great  reliance  is  placed  on  the  behavior 
of  the  leucocytes  in  connection  with  the  period  of  the  attack. 


302  GENERAL    HEMATOLOGY. 

Increase  in  the  purulent  focus,  and  extension  of  peritonitis  are 
betrayed  by  an  increase  in  the  leucocyte  count,  provided  that  the 
patient's  powers  of  reaction  are  not  too  greatly  crippled.  In 
operative  cases,  thorough  evacuation  of  the  abscess  is  followed 
within  a  few  days  by  a  decline  to  normal  in  the  number  of  leuco- 
cytes. Persistence  of  the  leucocytosis  after  the  third  or  fourth 
day  following  the  operation  may  usually  be  attributed  to  undrained 
pus  pockets  or  to  a  general  peritonitis. 

In  non-operative  cases  with  abscess  the  leucocytosis,  which 
becomes  well-developed  by  the  fourth  or  fifth  day  of  the  attack, 
persists  but  does  not  tend  to  increase  if  the  lesion  remains  local- 
ized ;  it  gradually  decreases  as  the  pus  collection  disappears  ; 
and  it  suddenly  increases  if  the  process  extends. 

To  sum  up,  absence  of,  or  slight,  leucocytosis  suggests  either  (a) 
simple  catarrhal  appendicitis,  (d)  fulminant  appendicitis,  or  (c)  a  lo- 
calized pus  focus  from  which  no  absorption  occurs.  Well-marked 
leucocytosis  indicates  either  (a)  a  local  abscess  from  which  ab- 
sorption of  toxins  occurs,  (d)  general  peritonitis,  or  [c)  gangrene. 

The  following  table  shows  the  range  of  the  leucocytes  in  the 
German  Hospital  cases  to  which  reference  has  been  made  : 


EUCOCYTES   PEF 

I    CB.  MM. 

N 

UMBER 

OF  Cases. 

L 

Non 

-puru 

lent. 

Purulent,  Peiforative,  and 
Gangrenous. 

Above  50,000 

0 

I 

From 

40,000  to 
35,000  to 

50,000 
40,000 

0 

0 

0 
2 

30,000  to 

35'Ooo 

0 

0 

25,000  to 
20,000  to 

30,000 
25,000 

0 
0 

6 
16 

15,000  to 

20,000 

4 

38 

10,000  to 
5,000  to 

15,000 

TO, 000 

10 

25 

24 
7 

Below 

'  5»ooo 

6 

0 

Highest  : 

17 

,100 

per 

cb. 

mm. 

58, 

500 

per  cb. 

mm. 

Lowest : 

I, 

600 

( i 

<< 

( ( 

6, 

000 

H          (( 

a 

Average : 

8 

987 

(( 

i  i 

<( 

17,955 

( (      (( 

(t 

The  qualitative  changes  found  in  high  leucocyte  counts  are 
those  typical  of  an  ordinaiy  polynuclear  neutrophile  leucocytosis 
— a  large  absolute  and  relative  gain  in  polynuclear  forms  at  the 
expense  of  the  hyaline  mononuclear  cells. 

The  conditions  which  may  more  or  less  closely 
Diagnosis,     simulate  an  acute  attack  of  appendicitis  are  nu- 
merous, and  unfortunately  it  happens  that  just 
those  lesions  in  which   the  resemblance   is  closest  often  produce 


APPENDICITIS.  303 

blood  changes  identical  with  those  of  appendicitis.  Thus,  leuco- 
cytosis  is  the  rule  in  pyosalpinx^  ovarian  abscess,  ectopic  pregnancy, 
pyonephrosis,  perinephritic  abscess,  hepatic  abscess,  empyema  of  the 
gall-bladder,  and  malignant  disease  of  the  cecum,  all  of  which 
may  be  confused  with  an  appendicular  abscess. 

Such  a  large  proportion  of  cases  of  hepatic  and  rental  colic  are 
accompanied  with  acute  inflammatory  complications,  giving  rise 
to  leucocytosis,  that  these  conditions  cannot  be  differentiated 
with  any  degree  of  confidence  from  appendicitis,  simply  by  an 
examination  of  the  blood.  The  same  is  true  of  dysmenorrhea, 
in  which  inflammatory  changes  in  the  uterus  may  constitute  the 
factor  of  a  leucocyte  increase.  Acute  gastritis  is  sometimes  ac- 
companied by  a  well-marked  leucocytosis,  and  sometimes  by 
none  at  all,  so  that  the  blood  count  cannot  be  relied  upon  as  a 
clue  in  distinguishing  this  disease  from  appendicitis. 

Simple  enteralgia,  and  ovarian  neuralgia  may  be  ruled  out, 
if  a  leucocyte  increase  is  present,  as  also  may  be  intestinal  ob- 
structio7i,  provided  that  the  latter  is  not  complicated  by  inflam- 
matory changes,  by  gangrene,  or  by  malignant  disease.  In 
lead-colic  there  is  often  a  pronounced  leucocytosis,  especially  in 
patients  with  acutely  toxic  symptoms  ;  but  granular  basophilia  of 
the  erythrocytes  can  be  detected  even  in  the  earliest  stages  of 
plumbism,  while  in  appendicitis  this  change  does  not  occur. 

The  presence  of  a  leucocytosis  is  sufficient  to  exclude  a  non- 
inflammatory ovarian  cyst,  and  a  movable  kidney,  and  the  same 
sign  is  of  no  little  value  in  ruling  out  enteiic  fever,  if  no  leuco- 
cyte-raising complications  are  apparent. 

The  simple  fact  of  the  presence  or  absence  of  a  leucocytosis  is 
more  often  misleading  than  useful  in  the  diagnosis  of  appendicitis, 
for  this  sign,  to  be  of  any  real  value,  must  invariably  be  corre- 
lated with  other  more  definite  clinical  manifestations.  Appendicitis 
should  never  be  ruled  out  because  leucocytosis  is  absent,  nor 
should  a  moderate  leucocyte  count  be  considered  an  indication  of 
the  benignancy  of  the  lesion.  A  count  in  excess  of  20,000  may 
be  relied  upon  as  a  certain  sign  of  pus  or  its  consequences,  and 
is  sufficient  to  warrant  operative  interference,  if  the  symptoms 
point  to  the  appendix  as  the  seat  of  the  trouble.  Counts  of  less 
than  20,000  cannot  be  depended  upon  to  reflect  the  character  of 
the  local  lesion,  since  an  increase  to  practically  this  figure  may  be 
found  occasionally  in  mild  catarrhal  cases,  as  well  as  in  those  with 
purulent  foci.  In  the  writer's  experience,  the  behavior  of  the 
leucocytes  throws  a  much  clearer  light  upon  the  progress  of  the 
disease,  in  both  operative  and  non-operative  cases,  than  it  does 
upon  the  initial  diagnosis,  which  should  be  determined  chiefly  by 
other  clinical  methods. 


;04  GENERAL    HEMATOLOGY. 


Vlir.    ASIATIC  CHOLERA. 

A  number  of  investigators  have  drawn  atten- 
General      tion  to  the  difficulty  met  with  in  many  cases  of 

Features,     obtaining  a  sufficient  quantity  of  blood  for  clin- 
ical   examination,  even    from    a    deep    puncture. 
This  peculiarity,  which  has  been  attributed  to  excessive  drj-ness 
of  the  tissues  from    drains  upon  the  body  fluids,  is   most    pro- 
nounced in  the  algid  stage  of  the  disease. 

The  great  decrease  in  the  alkalinity  of  the  blood  in  Asiatic 
cholera,  sometimes  spoken  of  as  an  acid  reaction,  was  first  de- 
termined by  C.  A.  Schmidt  ^  by  a  series  of  elaborate  analyses 
made  in  1850,  since  which  time  similar  findings  have  been  noted 
by  Cantani,'^  Straus,^  and  others. 

The  specific  gravity  of  the  blood-mass  is  found  to  be  increased, 
especially  in  those  cases  in  which  the  blood  is  highly  inspissated  ; 
in  such  instances  the  specific  gravity  may  rise  to  as  high  as  1073. 

The  agglutination  of  cholera  vibrios  by  the  blood  serum  of 
cholera  patients  was  first  applied  as  a  clinical  test  by  Achard 
and  Bensaude,^  these  investigators  finding  that  the  reaction  may 
occur  as  early  as  the  reputed  first  day  of  the  illness,  and  as  late 
as  the  fourth  week  after  recover^-.  Clinically,  the  test  may  be 
made  either  with  dried  blood  or  with  serum. 

The  studies  of  Biernacki  ^  and  of  Okladnych,^ 

Hemoglobin    which  together  include  the  investigation  of  sixty- 
AND  two  cases,  furnish  the  most  complete  data  con- 

Ervthrocytes.  cerning  the  changes  affecting  these  elements. 
Both  of  these  observers  found  a  more  or  less 
marked  polycythemia  with  a  proportionate  increase  in  the  hemo- 
globin percentage,  the  erythrocyte  count  in  many  cases  being 
between  6,500,000  and  7,500.000,  and  in  one  case  reaching  the 
remarkable  maximum  of  8,000,000.  The  increase  may  often  be 
observed  within  a  few  hours  after  the  onset  of  the  infection.  Con- 
centration of  the  blood  is  to  be  considered  as  the  cause  of  these 
high  counts,  which  are  as  a  rule  highest  in  cases  characterized 
by  pronounced  emesis  and  purging.  No  constant  relation  between 
the  degree  of  polycythemia  and  the  gravity  of  the  infection  can 
be  distinguished. 

^ '*  Charakteristik  der  epidemischen  Cholera  gegeniiber  verwandten  Transsuda- 
tionsanomileen,"  Leipsig,  1850. 

^Centralbl.  f.  die  med.  Wissenschaft. ,  1894,   vol.  xxii.,  p.  785. 
^Compt.  rend.  Soc.  biol.,  Paris,  1883,   vol.  iv.,  p.  569. 

*  Presse  med.,  1896,  vol.  xvi.,  p.  504. 

5  1)eut.  med.  Woch.,  1895,  vol.  xxi.,  p.  795. 

*  Cited  by  Biernacki :  loc.  cit. 


ASTHMA    AND    EMPHYSEMA.  305 

The  above-quoted  authors  found  high-grade 
Leucocytes,  leucocytosis  to  be  the  almost  invariable  rule, 
the  increase  in  leucocytes  being  not  parallel 
with,  but  rather  relatively  greater  than,  the  accompanying  in- 
crease in  erythrocytes.  It  occurs  both  in  mild  and  in  severe 
cases,  as  early  as  within  twelve  hours  after  the  onset  of  the  dis- 
ease, and  as  late  as  the  third,  fourth,  or  sixth  day.  It  may  be 
present  both  in  the  algid  stage  and  in  the  stage  of  reaction,  but  is 
likely  to  be  more  decided  in  the  former.  The  degree  of  leucocy- 
tosis may  range  from  a  minimum  count  of  14,000  to  a  maximum  of 
60,000  cells  per  cubic  millimeter,  the  case  of  average  severity 
showing  an  increase  to  about  25,000  or  30,000.  Pre-agonal 
leucocytosis  may  be  pronounced,  counts  of  50,000  being  not 
uncommon.  Biernacki  states  that  "  all  cases  which  in  the  algid 
stage  show  a  leucocytosis  of  40,000  to  60,000  soon  prove  fatal." 
On  the  contrary,  an  absence  of  leucocytosis  cannot  be  regarded 
as  a  surety  that  the  patient  will  recover.  In  a  trivial  infection 
distinct  leucopenia  has  been  observed,  but  this  is  rare.  Concen- 
tration of  the  blood  does  not  altogether  account  for  the  leucocy- 
tosis, for  the  influence  of  the  specific  infection  as  a  factor  is 
thought  to  be  most  active. 

The  leucocytosis  of  Asiatic  cholera  is  typically  polynuclear, 
the  increase  affecting  chiefly  the  polynuclear  neutrophile  cells, 
which  may  reach  relative  percentages  of  90  or  even  95,  while 
the  proportions  of  other  forms  are  lower  than  normal.  Sherring- 
ton ^  has  found  the  mast  cells  notably  increased  in  some  instances. 

IX.     ASTHMA  AND    EMPHYSEMA. 

In    long-standing   cases    moderate    secondary 

Hemoglobin    anemia  involving  chiefly  a  hemoglobin  loss  may 

AND  be  found,  for  in  many  instances  the  general  de- 

Erythrocytes.  bility  of  the  patient  or  the  presence  of  lesions  of 

other  organs  is  quite  adequate   to  give   rise  to 

such  a  change.      In  cyanotic  patients  the  anemia  may  be  hidden 

by  the  polycythemia  arising  from  circulatory  disturbances,  this 

deceptive  blood  concentration  being  most  conspicuous  during  an 

asthmatic  paroxysm. 

Little  or  no  increase  above  the  normal  stand- 
Leucocytes.    ard  in  the  number  of  leucocytes  is  the  usual  con- 
dition, although  these  cells  may  show  a  consid- 
erable increase  in  cases  associated  with  acute  bronchitis,  and  also 

^  Proc.  of  the  Roy.  Soc,  London,  1894,  vol.  Iv. ,  p.  189. 
20 


306  GENERAL    HEMATOLOGY. 

during  an  asthmatic  attack.  Gabritschewsky/  Fink,^  von  Noor- 
den,^  Billings/  and  others  have  called  attention  to  the  presence 
of  an  eosinophile  increase  in  both  asthma  and  emphysema. 
From  ID  to  20  per  cent,  of  this  type  of  cells  is  not  an  unusual 
proportion,  both  in  cases  with  and  those  without  leucocytosis, 
while  in  one  case  Billings  has  reported  three  consecutive  counts 
of  33.9,  38.2,  and  53.6  per  cent.,  respectively,  with  correspond- 
ing total  leucocyte  estimates  of  7,600,  7,500,  and  8,300  per  cubic 
millimeter.  In  true  bronchial  asthma  the  eosinophile  increase 
develops  shortly  before  the  paroxysm,  and  persists  during  and 
for  a  short  time  after  it,  disappearing  in  the  interval  between  the 
seizures.  This  sign  is  regarded  of  value  in  differentiating  true 
bronchial  asthma  from  the  dyspnea  due  to  renal  and  cardiac  le- 
sions, since  in  the  latter  the  eosinophiles  are  never  increased,  and 
it  is  also  considered  of  some  clinical  utilitv  in  heraldinsf  an 
impending  asthmatic  parox}'sm. 

X.      BRONCHITIS. 

TT  With  the  exception  of  a  sli";ht  oligochromemia, 

Hemoglobin      1  •  1    •     r  \.i  ^  ^  •       vi 

which  IS  irequently  present  m  severe  cases  with 

T-  ^  hi^h   temperatures,   the   eiythrocytes   and   their 

Erythrocytes.  ,  ^       ,  ,  v  ^    '  .  ^        J  ..  ,  . 

hemoglobin  content  remain  practically  normal  in 

all  forms  of  bronchial  inflammation. 

Acute  catarrlial  bronchitis  of  the  larger  tubes 
Leucocytes,  is  ordinarily  unattended  by  leucocytosis,  but,  un- 
fortunately for  diagnostic  purposes,  an  occasional 
case  shows  a  marked  increase.  Thus,  in  four  of  Cabot's  seventeen 
cases, ^  the  counts  were  17,600,  23,500,  26,000,  and  41,000,  re- 
spectively, while  in  eleven  the  leucocytes  numbered  more  than 
10,000  per  cubic  millimeter.  In  cJironic  brojicJiitis  leucocytosis 
rarely  if  ever  occurs.  The  range  of  the  leucocytes  in  capillary 
bronchitis  and  in  croupous  pneunioiiia  may  be  identical. 

XI.    BUBONIC    PLAGUE. 

Since  1 894,  when  Kitasato  and  Yersin,  working 
Bacteriolog-    independently, simultaneously  discovered  the  ^<7r//- 
ICAL  Exam-    lus  pcstis  buboniac  in  the  circulating  blood  of  pa- 
INATION.        tients  infected  with  plague,  this  organism  has  been 
repeatedly  isolated  from  the  blood  by  many  dif- 
ferent observ^ers.    In  a  bacteriological  study  of  twenty-seven  cases 

'  Archiv.  f.  exp.  Path.  u.  Pharm.,  1890,  vol.  xxviii.,  p.  ^t^. 

2  Inaug.  Diss.,  Bonn,  1890. 

^Zeitschr.  f.  klin.  Med.,  1S92,  vol.  xx.,  p.  98. 

♦  N.  Y.  Med.  Journ.,  1897,  vol.  Ixv.,  p.  691. 

^Loc.  cit. 


BUBONIC    PLAGUE.  3O7 

Ogata  ^  also  frequently  found  in  the  blood,  especially  in  severe  in- 
fections, a  micro-organism  morphologically  similar  to  Frankel's 
pneumococcus,  the  significance  of  this  unidentified  organism  being 
undetermined.  The  same  observer  calls  attention  to  the  fact  that 
blood  from  patients  convalescent  from  nineteen  to  sixty-five  days, 
although  giving  negative  results  by  cultural  methods,  when  in- 
jected into  mice  proves  rapidly  fatal  to  these  animals,  in  whose 
tissues  the  plague  bacillus  may  be  recovered  in  pure  culture.  The 
relatively  large  number  of  positive  results  to  be  obtained  from 
bacteriological  blood  examinations  in  this  disease,  especially  in  its 
septicemic  form,  attaches  to  the  procedure  no  small  diagnostic 
value.  Cultural  methods  with  blood  drawn  directly  from  a  vein 
give,  of  course,  the  most  favorable  results,  but  the  bacilli  may  be 
often  detected  in  the  stained  cover-glass  specimen  of  finger  blood, 
in  which  they  appear  as  short  rods,  tending  to  group  together  in 
chains  or  in  pairs,  exhibiting  bipolar  staining,  and  decolorizing  by 
Gram's  method.  In  view  of  the  fact  that  the  peripheral  blood 
contains  but  small  numbers  of  the  bacilH,  Rees^  advises  making 
large  films  on  slides  rather  than  cover-glass  specimens,  should 
direct  examination  of  the  stained  film  be  attempted. 

The  agglutination  of  the  plague  bacillus  by  the  blood  serum 
from  plague  subjects  has  been  noted  by  a  number  of  different 
investigators,  but  thus  far  no  clinical  application  of  the  reaction 
has  been  made.  The  inconstancy  with  which  the  reaction  occurs, 
for  it  may  frequently  be  absent  in  both  the  mildest  and  the  most 
severe  cases,  and  the  variable  degrees  of  serum  dilution  neces- 
sary for  its  production  appear  to  bar  the  acceptance  of  the  test  as 
a  rehable  diagnostic  sign. 

According  to  Aoyoma's  studies,^  the  hemo- 

Hemoglobin    globin  and  the  erythrocytes  are  both  decidedly 

AND  increased  above  normal  in  the  majority  of  cases. 

Erythrocytes.  Of  the  six  cases  examined  by  this  writer,  five 

showed  marked  polycythemia,  the  highest  count 
being  8, 190,000,  and  the  average  6,976,666.  Qualitative  changes 
in  the  erythrocytes,  it  is  to  be  presumed,  do  not  occur,  since  no 
mention  of  such  alterations  is  made. 

In  two-thirds  of  the  cases  just  quoted  marked 
Leucocytes,    increase  in  the  number  of  leucocytes  was  found, 

the  gain  being  greater  than  is  ordinarily  met  with 
in  any  condition  except  leukemia ;  the  count  exceeded  100,000 
in  four  instances,  and  averaged  for  the  six  96,666.     The  increase 

^Centralbl.  f.  Bakt.  u.  Parasit. ,  1897,  vol.  xxi.,p.  769. 

2  British  Med.  Journ.,  1900,  vol.  ii.,  p.  1236. 

3  Mittheilungen  aus  d.  Med.  Fac.  d.  Kaiserlich-Japanischen  Universitat,  Tokio, 
1895,  vol.  iii.,  p.  115. 


308  GENERAL    HEMATOLOGY. 

was  due  usually  to  a  disproportionately  large  percentage  of  poly- 
nuclear  neutrophiles,  but  in  some  cases  "  large  and  small  mono- 
nuclear white  cells"  were  observed.  The  identity  of  the  latter — 
whether  lymphocytes  or  myelocytes — must  remain  questionable, 
since  all  the  differential  counts  were  made  with  specimens  stained 
with  eosin  and  hematoxylin.  The  eosinophiles  were,  as  a  rule, 
conspicuous  by  their  absence. 

The  blood  plaques  were  found  to  be  notably  increased  in  number. 

XII.     CHOLELITHIASIS. 

In    gall-stone    complicated    by   phlegmonous 

General       cholangitis   or  other   purulent  sequelae,   hypcri- 

Features.       nosis  is  observ^ed,   and  coagulation  is  generally 

more  rapid  than  normal,  but  in  simple  impacted 

calculi  these  changes  are  absent.     The  general  effects  upon  the 

blood  of  bile,  elsewhere  noted,  may  also  be  detected  when  marked 

jaundice  develops.     (See  *'Cholemia"  and  "Icterus.") 

Positive  results  from  bacteriological  exami?iation  of  the  blood 
have  frequently  been  obtained  in  cholelithiasis,  streptococci  hav- 
ing been  isolated  by  Netter,^  staphylococci  and  colon  bacilli  by 
Sittmann,"  streptococci  and  pneumococci  by  Canon, ^  and  various 
bacteria  of  unknown  identity  by  other  investigators. 

Moderate    oligochromemia    is    found    in    the 
Hemoglobin    greater  proportion  of  cases,  but  a  decided  loss 
AND  either  of  hemoglobin  or  of  erythrocytes  is  com- 

Erythrocytes.  paratively  rare.  In  general  terms,  it  may  be 
conservatively  stated  that  the  hemoglobin  loss 
on  the  average  amounts  to  about  30  per  cent.,  and  that  the  cel- 
lular decrease  approximates  15  per  cent,  of  the  normal  standard. 
In  occasional  instances,  notably  those  in  which  suppuration  or 
sepsis  coexists,  the  anemia  is  of  a  more  intense  grade,  and  may 
be  associated  with  various  changes  indicative  of  cellular  degen- 
eration. In  28  cases  of  cholelithiasis  at  the  German  Hospital  the 
following  estimates  of  the  hemoglobin  and  erythrocytes  were 
obtained  at  the  initial  examinations  : 


Hemoglobin- 
Percentage. 

From  80  to  90 

'*     70  to  80 

Number 
Cases. 

5 
10 

of 

Above 
From 

Erythrocytes 
per  cb.  mm. 

5,000,000 

4,000,000  to  5,000,000 

N 

umber  of 
Cases. 

3 
13 

*'     60  to  70 

8 

a 

3,000,000  to  4,000,000 

10 

"     50  to  60 

4 

(C 

2,000,000  to  3,000,000 

2 

*'     40  to  50 
**     30  to  40 
"      20  to  30 

0 
0 

I 

^  Progres  med.,  i8S6,  vol.  xiv.,  p.  992. 

2  Deut.  Archiv.  f.  klin.  Med.,  1894,  vol.  liii.,  p.  323. 

3  Deut.  med.  Woch.,  1893,  vol.  xix.,  p.  1038. 


DIABETES    MELLITUS.  3O9 

Average:       70.6  per  cent.  Average:       4,131,785  per  cb.  mm. 

Maximum:    85.0       •''  Maximum:    5,390,000        "      " 

Minimum:    28.0       '*  Minimum:    2,510,000        *'      ^' 

Simple  gall-stone  does  not  of  itself  excite  the 
Leucocytes,  slightest  increase  in  the  number  of  leucocytes, 
but  nevertheless  leucocytosis,  typically  polynu- 
clear  in  type,  is  a  rather  common  feature  of  the  blood -picture  in 
this  disease,  owing  to  the  fact  that  such  a  large  percentage  of 
cases  is  complicated  by  acute  inflammatoiy  changes.  Ten  of 
the  28  cases  just  mentioned  had  a  count  of  more  than  10,000 
cells  to  the  cubic  millimeter.  The  following  resume  of  the  ex- 
aminations illustrates  the  range  of  leucocytes  in  the  series  : 

Leucocytes  per  cb.  mm. 

From  15,000  to  20,000  in     7  cases. 

"     10,000  to  15,000   ^'     3      '' 

"        5,000  to  10,000   "  16      ^' 
Below  5,000  "  2      '' 

Average  :       10,164  P^r  cb.  mm. 
Maximum:    18,800    "     "       " 
Minimum:      4,600    "     '*      '^ 

The  presence  of  a  leucocytosis  excludes  simple 
Diagnosis.      biliary  coHc,  and  indicates  as  the  cause  of  the  in- 
crease some  other  lesion,  such,  for  example,  as 
phlegmonous  cholangitis  or  cholecystitis,  hepatic  abscess,  peritonitis, 
or  malignant  disease.     Hepatic  and  renal  colics  cannot  be  differ- 
entiated by  the  blood  count, 

XIII.     DIABETES    MELLITUS. 

The  alkalinity  of  the  blood,  according  to  the 
General       general    consensus    of    opinion,    is    appreciably 
Features.      diminished,  especially  in   cases   in   which   coma 
either  impends  or  exists.     Lipeniia  is  not  uncom- 
mon, the  amount  of  fat  in  some  instances  being  so  large  as  to  pro- 
duce a  milky  appearance  of  the  blood  drop,  evident  to  the  naked 
eye,  although  in  most  instances  the  condition  is  recognizable  only 
by  the  detection  of  fat-globules  under  the  microscope.      Lipaci- 
deniia  may  be  detected  in  diabetic  coma.     Glycemia  is  present,  and 
can  be  demonstrated  by  the  detection  of  grape-sugar  in  relatively 
large  amounts,  even  as  great  as  5.7  parts  per  thousand,  according 
to  Grawitz,^  or  9  parts  per  thousand,  according  to  Hoppe-Seyler.^ 
Williamson' s  Test.     This  reaction,  devised  by  Williamson  ^  in 

'  Loc.  cit. 

2Vircho\v's  Archiv.,  1858,  vol.  xiii.,  p.  104. 

3  British  Med.  Journ.,  1896,  voL  ii.,  p.  730.     Also,  Lancet,  1900,  vol.  ii.,  p.  320. 


3IO 


GENERAL    HEMATOLOGY. 


1896,  depends  upon  the  fact  that  a  warm  alkaHne  solution  of 
methylene-blue  is  decolorized  when  mixed  with  a  minute  quantity 
of  glucose.  Twenty  cubic  millimeters  of  the  suspected  blood, 
obtained  by  puncturing  the  finger,  are  measured  by  means  of 
Gower's  hemocytometer  pipette,  and  blown  out  into  40  cubic 
millimeters  of  distilled  water  contained  in  a  small  test-tube.  To 
this  mixture  are  then  added,  in  the  order  given,  i  cubic  centi- 
meter of  a  I  :  6,000  aqueous  solution  of  methylene-blue,  and  40 
cubic  millirrieters  of  a  six-per-cent.  aqueous  solution  of  potassium 
hydrate.  In  a  second  test-tube  the  same  proportions  of  normal 
blood  and  reagents  are  mixed,  to  be  used  as  a  control.  The 
color  of  both  mixtures  is  precisely  the  same — moderately  deep 
bluish-green.  Both  tubes  are  placed  in  a  beaker  filled  with  boil- 
ing water,  in  which  they  are  allowed  to  remain  for  four  minutes, 
at  the  end  of  which  time  the  test-fluid  containing  the  diabetic 
blood  will  have  turned  a  dingy  yellow  color,  while  the  color  of 
the  control  mixture  remains  unchanged.  Care  must  be  taken  to 
use  not  more  than  20  cubic  millimeters  of  blood,  since  a  positive 
reaction  may  be  more  or  less  closely  counterfeited  with  non-dia- 
betic blood,  should  three  or  four  times  this  quantity  be  employed. 
It  IS  essential,  therefore,  to  measure  the  blood  accurately,  and 
not  to  trust  to  the  approximate  method  used  by  some,  of  simply 
taking  two  drops  of  blood  as  the  equivalent  of  the  required  20 
cubic  millimeters. 

Williamson's  reaction  is  presumably  due  solely  to  the  action  of 
the  grape-sugar  contained  in  diabetic  blood,  and  if  this  proves 
true,  it  is  not  unreasonable  to  predict  that  the  principle  of  the  test 
may  be  elaborated  into  a  method  for  estimating  the  percentage 
of  sugar  in  the  blood.  Positive  reactions  occur  constantly  in 
diabetes,  sometimes  even  after  the  disappearance  of  every  trace 
of  sugar  from  the  urine,  and,  so  far  as  investigations  up  to  the 
present  time  have  shown,  negative  results  are  invariably  met  with 
in  other  diseases. 

Bremer's  Test.  Bremer,^  having  noticed  in  diabetes  mellitus 
peculiar  affinities  of  the  erythrocytes  for  various  aniline  dyes,  has 
devised  upon  this  basis  an  ingenious  test  for  the  recognition  of 
diabetic  blood.  Several  thick  films  from  a  suspected  case,  con- 
trolled by  the  same  number  of  preparations  made  from  normal 
blood,  are  prepared,  preferably  on  slides,  and  heated  in  an  oven 
to  a  temperature  of  135°  C,  after  which  they  are  set  aside  to 
cool.  Both  sets  of  films  are  then  stained  for  about  two  minutes 
with  a  one-per-cent.  aqueous  solution  of  Congo-red  (mixed  freshly 

1  N.  Y.  Med.  Journ.,  1S96,  vol.  Ixiii.,  p.  301.     (Z//. )     Also  N.  Y.  Med.  Record, 

1897,  vol.  xii.,  p.  495. 


DIABETES    MELLITUS.  3  I  I 

just  before  using),  thoroughly  washed  in  running  water,  and 
dried  between  bits  of  filter-paper.  Thus  treated,  diabetic  blood 
is  either  colored  pale  greenish-yellow  or  is  entirely  unstained, 
while  normal  blood  stains  typically  the  red  color  of  the  dye. 
Using  the  same  method  of  heat  fixation,  other  aniline  dyes  may 
be  employed  to  demonstrate  this  peculiar  behavior  of  diabetic 
blood.  For  example,  with  a  one-per-cent.  aqueous  solution  of 
methylene-blue  the  diabetic  specimen  stains  yellowish-green,  and 
the  normal  film  blue.  Diabetic  blood,  on  the  contrary,  treated 
with  a  one-per-cent.  aqueous  solution  of  biebrich-scarlet,  takes 
the  color  of  the  dye  in  a  typical  manner,  while  normal  blood  re- 
mains practically  uncolored.  Ehrlich's  triacid  stain,  as  well  as 
mixtures  of  methylene-blue  and  eosin,  and  methyl-green  and 
eosin,  have  also  been  used  to  demonstrate  the  reaction.  The 
cause  of  Bremer's  reaction  is  unknown,  but  apparently  it  is  not 
due  to  the  effect  of  glucose  ;  many  authors  are  inclined  to  attrib- 
ute it  to  excessive  acidity  of  the  blood.  Positive  results  with 
this  test  can  not  be  regarded  as  pathognomonic  of  diabetes  mel- 
Htus,  since  they  have  been  reported  with  the  blood  of  persons  suf- 
fering from  exophthalmic  goitre,  multiple  neuritis,  leukemia,  and 
Hodgkin's  disease. 

There  are  no  constant  changes  to  be  found  in 
Hemoglobin    these   elements.     Normal   hemoglobin    percent- 
AND  ages   and   erythrocyte   counts    are    observed    in 

Erythrocytes,  most  cases,  while  in  others  in  which  the  cachexia 
is  pronounced,  a  well-marked  secondary  anemia 
may  exist.  James,^  in  a  study  of  1 3  cases,  found  the  number 
of  erythrocytes  over  6,000,000  in  5  ;  5,000,000  plus  in  5  ;  4,000, - 
000  plus  in  2;  and  3,000,000  plus  in  i.  The  hemoglobin  per- 
centage was  over  100  in  3  cases  ;  60-70  in  8  ;  and  50-60  in  2. 
The  alterations  in  the  hemoglobin  and  erythrocytes  in  diabetes 
have  been  attributed  by  the  older  writers^  chiefly  to  the  effects  of 
blood  concentration  and  dilution.  Thus,  it  was  beHeved  that  in 
cases  with  excessive  polyuria  the  blood  became  inspissated  and 
the  count  thus  increased,  while  in  cases  with  pronounced  gly- 
cemia  the  blood  became  diluted  and  the  count  lowered,  as  a  con- 
sequence of  the  fluid  transfer  from  the  tissues  into  the  capillaries 
provoked  by  the  presence  in  the  blood  of  a  large  percentage  of 
sugar.  It  is  obvious  that  these  influences,  if  active,  are  sufficient 
to  render  the  blood  count  in  diabetes  of  little  or  no  practical 
value,  since  on  the  one  hand,  perfectly  normal  blood,  if  diluted, 

1  Edinburgh  Med.  Journ.,  1896,  vol.  xlii.,  p.  193. 

2  Lit.  cited  by  Leichtenstern  :   "  Unters.   uber  d.  Hg-Gehalt  d.  Blutes,"  Leipzig, 
1878. 


312  GENERAL    HEMATOLOGY. 

may  appear  anemic,  while  on  the  other  hand,  anemic  blood,  if 
concentrated,  may  seem  normal.  James  ^  contends,  however, 
that  the  polycythemia  is  real,  and  is  not  dependent  upon  inspis- 
sation,  for  were  the  increase  merely  relative  it  would  naturally  be 
accompanied  by  an  increase  in  the  density  of  the  blood,  and  this 
in  his  experience  never  occurred,  the  specific  gravity  figure  for 
his  series  ranging  between  1054  and  1060. 

High  digestion  leucocytosis  is  the  most  con- 
Leucocytes.  stant  change  affecting  these  cells,  but  this  is  not 
found  in  every  case.  Isolated  examples  of  leu- 
coc\tosis,  apparently  independent  of  this  influence,  have  been  re- 
ported, but  in  the  great  majorit}'  of  diabetics  the  leucocyte  count 
is  normal.  The  presence  of  small  numbers  of  myelocytes  in 
cachectic  patients  is  the  only  qualitative  change  to  which  atten- 
tion has  been  directed.  ]\Iahogany-colored  granules,  either  within 
the  leucocytes  or  extracellular,  may  usually  be  demonstrated  by 
the  iodine  method.  The  prevalent  view  that  this  reaction  is  due 
to  the  presence  of  glycogen  has  been  disputed  by  some  (see  page 

No  numerical  change  in  the  blood  plaques  has  been  reported. 

Williamson's  reaction  is  of  real  value,  especially 
Diagnosis,     in  the  recognition  of  cases  with  temporar}^  disap- 
pearance of   sugar  from   the   urine  and  in  dia- 
betic  coma.     Bremer's  test  and  the   iodine  reaction   are    to  be 
regarded  as    symptomatic,   not    necessarily   of    diabetes.      The 
other  blood  findings  are  without  diagnostic  value. 

XIV.     DIPHTHERIA. 

Usually  the   changes  in  the  hemoglobin  and 
Hemoglobin    erj^throcytes    are,   at   the   most,    trifling,   for    in 
AND  about  two-thirds  of  all  cases  these  elements  are 

Erythrocytes,  practically  normal,  while  in  the  other  one-third 
moderate  anemia,  more  marked  in  severe  than 
in  mild  cases,  is  found.  The  anemia  does  not  develop  until 
about  the  middle  of  the  first  week  of  the  disease,  and  is  as  a 
rule  characterized  by  a  diminution  of  hemoglobin  roughly  pro- 
portionate to  the  corpuscular  loss.  Degenerative  changes  are  rare, 
consisting  usually  of  nothing  more  than  occasional  polychromato- 
philia  ;  nucleation  and  deformities  of  size  and  of  shape  are  absent. 
Regeneration  of  the  blood  takes  place  slowly,  and.  as  the  loss  of 
hemoglobin  is  made  up  less  rapidly  than  that  of  the  corpuscles, 
the  color  index,  which  is  approximately  normal  early  in  the  dis- 
ease, later  falls  considerably. 

1  Loc.  cit. 


DIPHTHERIA.  3I3 

The  loss  of  hemoglobin  does  not  often  exceed  15  per  cent., 
nor  is  the  decrease  of  eiythrocytes  usually  greater  than  from 
500,000  to  750,000  cells  to  the  cubic  millimeter.  Concentration 
of  the  blood,  which  frequently  occurs  during  the  febrile  period, 
may  cause  striking  temporary  polycythemia. 

Morse  ^  in  single  examinations  of  30  cases,  treated  without 
antitoxin,  found  the  count  of  erythrocytes  above  5,000,000  in 
21,  and  below  4,000,000  in  but  a  single  instance,  a  woman  with 
chronic  anemia ;  several  of  his  counts  were  in  the  neighborhood 
of  6,000,000.  From  this  author's  recent  monograph^  the  fol- 
lowing counts  reported  by  other  investigators  are  taken  :  Bouchut 
and  Dubroisay,^  4,305,000  as  the  mean  average  of  93  counts  in 
84  cases  ;  Gilbert,*  an  average  of  4,500,000  in  58  counts  in  22 
cases;  Carter,^  an  average  of  4,253,000  in  13  cases;  and  File,^  an 
average  of  4,588,000  in  18  counts  in  10  cases,  some  of  which  had 
received  antitoxin.  Billings  ^  in  a  painstaking  study  of  7  cases, 
untreated  with  antitoxin,  in  which  36  counts  were  made,  found  a 
moderate  but  distinct  decrease  in  hemoglobin  and  eiythrocytes 
in  5  cases,  the  loss  first  becoming  apparent  by  the  third  or 
fourth  day,  and  being  proportionate  to  the  severity  of  the  infec- 
tion. This  author's  first  counts,  all  made  during  the  first  week 
of  the  disease,  ranged  from  5,200,000  to  6,122,000,  the  average 
being  5,611,285,  the  hemoglobin  for  the  same  period  ranging 
from  70  to  98  per  cent,  and  averaging  90  per  cent.  Subsequent 
counts  in  this  series  showed  that  the  greatest  loss  of  hemoglobin 
averaged  12  per  cent.,  ranging  from  i  to  30  per  cent.,  and  that 
the  maximum  corpuscular  loss  averaged  878,500,  varying  from 
227,000  to  2,040,000. 

It  is  generally  observed  that  in  cases  treated  with  antitoxin 
the  anemia  is  decidedly  less  than  in  those  treated  by  other 
methods,  and  in  fact  a  majority  of  cases  thus  treated  suffer  no 
decrease  at  all. 

Well-marked  leucocytosis,  beginning  probably 

Leucocytes,    within  a  few  hours  after  the  infection  first  occurs, 

characterizes  the  average  case  of  diphtheria  of 

moderate  severity.     An  analysis  of  the  statistics  derived  from  276 

counts  made  by  reliable  investigators^  shows  that  over  90  per 

1  Boston  Med.  and  Surg.  Journ. ,  1895,  vol.  cxxxii.,  pp.  228  and  252. 

2  Med.  and  Surg.  Reports  of  the  Boston  City  Hospital,  1899,  loth  series,  p.  138. 

3  Compt.  rend.  Soc.  biol.,  Paris,  1877,  vol.  Ixxxv.,  p.  158. 
*  Traite  de  Med.  Charcot- Bouchard,  vol.  ii.,  p.  485. 

5  Univ.  Med.  Mag.,  1894-95,  vol.  vii.,  pp.  17,  81,  and  158. 
^  Lo  Sperimentale,  1896,  vol.  1.,  p.  284. 
^  N.  Y.  Med.  Record,  1896,  vol.  xlix.,  p.  577. 

^Ewing,  Morse,  Billings,  Carter,  Schlesinger,  File,  Gabritschewsky,  Bouchut  and 
Dubroisay,  Rieder,  Felsenthal,  and  Gilbert. 


314  GENERAL    HEMATOLOGY. 

cent,   of  all  cases  are  accompanied  by  a  more  or  less  marked 
increase  in  the  number  of  leucocytes. 

In  the  majority  of  cases  the  number  of  leucocytes  is  not  in- 
creased above  30,000  per  cubic  millimeter,  but  a  much  greater 
leucocytosis  is  sometimes  encountered.  Thus,  the  maximum 
counts  of  sev^eral  authors  are  as  follows  :  Felsenthal,  148,229;^ 
Ewing,  72,000;"  Gabritschewsky,  51,000;^  Morse,  48,000;'* 
Carter,  48,280;^  Billings,  38,600;''  and  Gilbert,  31,000.^ 

This  increase  is  to  be  regarded  as  a  rough  gauge  of  the  reac- 
tion of  the  individual  against  the  effects  of  the  toxic  products  of 
the  disease  ;  it  is,  therefore,  absent  in  very  mild  cases,  where  little 
or  no  reaction  is  excited,  and  in  veiy  severe  cases  in  which  the 
patient's  resisting  powers  are  overwhelmed  by  the  intoxication. 

In  favorable  cases  the  maximum  leucocytosis  is  reached  coin- 
cidentally  with  the  height  of  the  disease,  and  the  increase  gradually 
fades  away  during  convalescence,  having  in  most  cases  entirely 
ceased  by  the  time  the  membrane  has  disappeared,  but  occa- 
sionally persisting  after  the  subsidence  of  all  local  and  systemic 
manifestations  of  the  illness.  In  unfavorable  cases  high  leucocyte 
counts  persist  until  death,  or  ''  in  somewhat  prolonged  cases, 
with  much  septic  absorption,  there  may  be  an  uninterrupted 
decrease  of  leucocytes  continuing  up  to  the  fatal  termination." 
(Ewing.)  No  constant  relation  has  been  determined  between  the 
leucocytosis  and  the  extent  of  the  local  lesion,  the  degree  of 
tonsillar  and  glandular  swellings,  or  the  height  of  the  fever, 
although  in  individual  cases  some  authors  have  suggested  that 
such  relationship  may  be  distinguished. 

The  effects  of  antitoxin  upon  the  leucocytes  are  well  illustrated 
by  the  conclusions  of  Ewing,"*  based  upon  228  counts  made  in  53 
cases,  before  and  after  the  injection  of  the  serum.  As  the  result 
of  these  investigations  this  author  concludes  that  antitoxin,  within 
thirty  minutes  after  its  injection,  causes  a  hypoleucocytosis.  In 
favorable  cases,  after  the  injection,  the  original  height  of  the 
leucocytosis  is  not  again  attained,  but  in  severe  and  less  favor- 
able cases,  the  dose  of  antitoxin  is  followed  in  a  few  hours  by 
a  hyperleucocytosis  exceeding  that  found  in  the  primar\^  count. 
In  malignant  cases  the  administration  of  antitoxin  may  be  fol- 
lowed immediately  either  by  rapid  hyperleucocytosis  or  by  ex- 
treme hypoleucocytosis  and  death.  Bize^  finds  that  in  some 
cases  the  initial  serum  injection  may  not  affect  the  leucocytes  be- 

^Archiv.  f.  Kinderheilk.,  1893,  vol.  xv.,  p.  78. 
2N.  Y.  Med.  Joum.,  1S93,  vol.  Iviii.,  p.  713. 
3Annal.  de  llnstitut  Pasteur,  1 894,  vol.  viii.,  p.  673. 
*  Loc.  cit. 
^Archiv.  de  med.  des  enf.,  1901,  vol.  iv.,  p.  102. 


DIPHTHERIA.  315 

cause  of  the  insufficiency  of  the  dose,  and  that  repeated  injections 
are  sometimes  required  to  modify  the  count.  This  investigator 
has  also  called  attention  to  the  pronounced  leucocytoses  which 
accompany  eruptions  due  to  antitoxin. 

The  leucocytosis  of  diphtheria  as  a  rule  involves  the  polynu- 
"clear  neutrophile  cells,  most  cases  showing  about  80  per  cent, 
of  this  variety,  but  in  an  occasional  instance  there  may  be  a 
well-marked  increase  in  the  mononuclear  forms,  considerably  in 
excess  of  the  percentage  found  in  health.  Relative  lymphocy- 
tosis has  been  observed  both  during  convalescence  and  in  fatal 
cases  with  leucopenia,  and  absolute  lymphocytosis  may  occur  at 
the  height  of  the  disease  in  cases  with  high  total  leucocyte  counts. 

Besredka  ^  believes  that  marked  polynuclear  leucocytosis  is  a 
good  prognostic  sign,  especially  if  this  form  of  cells  shows  a 
strong  tendency  to  increase  after  injection  of  antitoxin.  On  the 
contrary,  cases  which  fail  to  show  such  a  change  he  regards  as 
grave,  usually  as  fatal.  This  characteristic  of  high  percentages 
of  polynuclear  neutrophils  is  also  regarded  by  many  other 
authors  as  a  favorable  chnical  sign,  and  a  low  percentage  un- 
favorable. 

Ewing,  ^  by  staining  the  leucocytes  with  gentian-violet  (50  cc. 
of  normal  salt  solution  to  which  i  drop  of  a  saturated  alcohoHc 
solution  of  gentian-violet  is  added),  has  deduced  certain  conclu- 
sions from  the  reaction  of  the  leucocytes  to  this  dye,  to  which  he 
is  inclined  to  attribute  great  prognostic  value.  He  believes  that 
the  numbers  and  percentages  of  poorly  stained  leucocytes,  and 
usually  of  ameboid  figures,  invariably  increase  in  unfavorable 
cases,  without  relation  to  the  total  number  of  cells  found  in  the 
blood.  In  his  experience  any  considerable  increase  of  poorly 
stained  leucocytes,  especially  if  associated  with  a  decrease  of  the 
well-stained  cells,  was  invariably  the  forerunner  of  a  grave  or 
fatal  change  in  the  patient's  condition.  In  favorable  cases,  after 
treatment  with  antitoxin,  he  noted  that  the  polymorphous  forms 
show  a  decidedly  increased  affinity  for  gentian-violet,  this  char- 
acteristic often  being  observed  within  twelve  hours  after  the  in- 
jection of  the  serum.  Failure  of  this  peculiarity  to  develop  he 
regards  as  a  very  unfavorable  prognostic  sign.  Up  to  the  present 
time  these  observations  have  not  been  verified  by  other  investi- 
gators. 

The  proportion  of  eosinophiles  is  exceedingly  variable,  these 
cells  sometimes  being  absent,  and  at  other  times  found  in  large 
numbers — 4  or  5  per  cent. 

^Annal.  de  I'lnstitut  Pasteur,  1S98,  vol.  xii.,  p.  305. 
2  Loc.  cit. 


3l6  .  GENERAL    HEMATOLOGY. 

Engel  ^  found  variable  percentages  of  myelocytes  in  both  favor- 
able and  unfavorable  cases,  especially  in  the  latter,  and  he  con- 
siders the  presence  of  these  cells  in  relatively  high  percentages 
(2  per  cent,  or  higher)  as  an  unfavorable  prognostic  indication. 
In  7  of  Engel' s  fatal  cases  the  percentage  of  myelocytes  ranged 
from  3.6  to  14.6,  but  these  cells  never  exceeded  1.5  per  cent,  in 
patients  who  recovered.  An  absence  of  myelemia,  however,  is 
no  guarantee  of  recover}^  for  this  sign  is  absent  in  about  one  out 
of  every  four  fatal  cases. 

Examination  of  the  blood  in  diphtheria  gives 

Diagnosis,     no  information  which  is  not  more  clearly  shown 

by  other  clinical  signs,  and  it  must  be  regarded 

as  of  no  value  as  an  aid  to  diagnosis.     The  leucocytosis  in  this 

disease,  if  the  very  benign  and  the  very  severe  cases  are  excluded,. 

is,  as  a  rule,  proportionate  to  the  intensity  of  the  infection. 

From  a  prognostic  point  of  view,  it  appears  that,  as  in  pneu- 
monia, an  absence  of  leucocytosis  occurring  in  obviously  severe 
infections  is  an  unfavorable  indication.  The  presence  of  a  large 
percentage  of  myelocytes  has  a  similar  meaning.  Pronounced 
lymphocytosis  is  also  regarded  as  an  unfavorable  prognostic 
sign. 

XV.     ENTERITIS. 

In  acute  catarrhal  enteritis  the  same  changes  occur  that  are 
found  in  acute  gastritis,  namely,  little  or  no  alteration  in  the 
hemoglobin  and  eiythrocytes,  and  an  inconstant,  moderate  leuco- 
cytosis. Profuse  watery  dejecta  lead,  of  course,  to  more  or  less 
blood  concentration,  by  depletion  of  the  body  fluids,  and  hence 
polycythemia  may  be  a  transient  sign.  In  cJironic  enteritis  and 
gastro-euteritis,  the  interference  with  the  patient's  nutrition  plus  a 
drain  upon  the  albuminoids  may  in  course  of  time  give  rise  to  a 
decided  anemia.  Leucocytosis  is  not  a  characteristic  of  such 
cases.  In  dysentery  and  in  itlcerative  and  pJilegnionous  enteritis, 
acute  forms  of  secondary  anemia  are  frequently  met  with,  espe- 
cially in  patients  who  pass  much  blood  by  the  bowel. 

The  effects  upon  the  blood  of  saline  purges  were  first  deter- 
mined by  Brouardel,"  and  later  studied  by  Grawitz  ^  and  by  Hay.^ 
The  investigations  of  these  authors  have  shown  that  the  adminis- 
tration of  a  purgative  dose  of  Epsom  or  Glauber  salt  is  followed 
within  about  thirty  minutes  by  an  appreciable  increase  in  the 
number  of  erythrocytes,  and  that  within  an  hour  the  count  of 

^  Deut.  med.  Woch.,  1S97,  vol.  xxiii.,  pp.  iiS  and  137. 

2 Union  med.,  1S97,  vol.  xxii.,  p.  405. 

3  Loc.  cit. 

*  Journ.  of  Anat.  and  Physiol.,  1SS2,  vol.  xvi.,  p.  430. 


ENTERIC    FEVER.  317 

these  cells  is  fully  1,500,000  more  than  before  the  purge  was 
given  ;  three  hours  after  this  maximum  is  reached  the  count  is 
again  normal.  When  a  certain  degree  of  concentration  is  ob- 
tamed  by  this  means,  continued  administration  of  the  salt  pro- 
duces neither  additional  concentration  nor  further  purgation. 
Common  table  salt  is  also  a  most  energetic  factor  of  blood  den- 
sity, even  more  so  than  either  Epsom  or  Glauber  salts.  Purga- 
tive doses  of  jalap,  croton  oil,  and  other  drugs  of  this  class  are 
also  followed  by  more  or  less  polycythemia. 

XVI.     ENTERIC    FEVER. 

Invasion  of  the  blood  by  the  bacillus  typhosus 
Bacteriology,  is  of  such  relatively  uncommon  occurrence  that 
bacteriological  examinations  in  enteric  fever,  for 
diagnostic  purposes,  are  of  slight  practical  value.  From  an 
analysis  of  210  cases  examined  by  reliable  investigators,  using 
approved  technique,  the  specific  organism  of  the  disease  was  ob- 
tained by  culture  in  but  78  instances — an  average  of  37  per  cent, 
of  positive  results  in  all  cases.  These  figures,  however,  should  be 
applied  only  to  the  average,  and  not  to  the  individual  case,  for 
many  competent  workers  have  obtained  lower  averages,  or  have 
been  uniformly  unsuccessful  in  attempting  to  isolate  the  bacillus 
from  the  blood,  while  others  have  reported  much  higher  per- 
centages of  successful  results. 

Kiihnau  ^  made  cultures  in  41  cases,  of  which  number  positive 
results  were  obtained  in  1 1 .  James  and  Tuttle  ^  carefully  examined 
39  cases,  and  succeeded  in  obtaining  the  organism  in  3.  V^ilt- 
schour,^  in  his  examinations  of  35  cases,  found  the  bacillus  in 
only  a  single  instance.  Of  16  cases  examined  by  Castellani,"* 
blood  cultures  were  positive  in  4 ;  of  the  patients  giving  positive 
findings,  3  died.  Opposed  to  the  foregoing  results  are  the  unusu- 
ally high  percentages  of  positive  findings  reported  by  Cole,^  who 
used  from  8  to  10  cubic  centimeters  of  blood,  aspirated  from  a 
vein  of  the  arm.  This  investigator  obtained  growths  of  the  bacil- 
lus in  1 1  of  the  i  5  cases  examined,  positive  results  being  found 
as  early  as  the  sixth  day  of  the  disease,  in  both  mild  and  severe 
cases.  Schottmijller^  also  reports  an  unusually  high  proportion 
of  successful  findings,  this  investigator  having  isolated  the  typhoid 
bacillus  in  40  out  of  50  cases  whose  blood  he  examined.     Thie- 

^  Zeitschr.  f.  Hyg.  u.  Infectionskr.,  1897,  vol.  xxv.,  p.  492. 

2  Med.  and  Surg.  Reports  of  the  Presbyterian  Hosp.,  N.  Y.,  1898,  vol.  iii.,  p.  46. 

3  Rev.  Centralbl.  f.  Bakteriol.  u.  Parasit.,  1890,  vol.  xiv.,  p.  279. 
*Centralbl.  f.  Allg.  Path.  u.  pathol.  Anat.,  1900,  vol.  xi.,  p.  456. 
5 Johns  Hopkins  Hosp.  Bull.,  1901,  vol.  xii.,  p.  203. 

^Deut.  med.  Woch.,  1900,  vol.  xxvi.,  p.  511. 


3l8  GENERAL    HEMATOLOGY. 

mich  ^  studied  7  cases,  with  positive  results  in  4 — in  a  single  in- 
stance from  venous  blood,  and  in  3  from  the  rose-spots.  Stern  ^ 
investigated  6  cases,  obtaining  growths  in  3,  the  bacillus  being 
isolated  from  the  rose-spots  in  one,  and  from  the  blood  in  the 
other  2.  Gwyn  ^  has  recently  reported  a  case  with  typical  clinical 
manifestations  of  enteric  fever,  in  which  he  obtained  cultures, 
made  from  the  blood  at  the  height  of  the  disease,  of  a  bacillus 
having  cultural  properties  almost  identical  with  the  para-colon 
bacillus  of  Widal.  In  the  late  stages  of  the  disease  pyogenic 
bacteria  have  been  found  in  the  blood. 

Examination  of  the  Rose-spots.  Formerly  the  cultivation  of 
typhoid  bacilli  from  the  rose-spots  was  attended  by  indiffer- 
ent success,  but  the  favorable  results  with  this  procedure  recently 
announced  by  a  number  of  authors  must  stamp  it  as  a  distinct  aid 
to  the  diagnosis  of  typhoid.  Neufeld,"*  basing  his  experiments 
upon  the  belief  that  the  bacteria  lodge  and  multiply  in  the  spots 
protected  from  the  bactericidal  action  of  the  blood,  examined 
these  lesions  in  14  cases  and  obtained  positive  results  in  13.  His 
findings  were  soon  corroborated  by  the  work  of  Curschmann," 
who  found  the  bacilli  in  14  out  of  20  cases  ;  of  Richardson,^  whose 
results  Vvcre  positive  in  5  out  of  6  cases  ;  and  of  Scholz  and 
Krause,'  who  found  bacilli  in  the  spots  in  14  out  of  16  cases  ex- 
amined. The  latter  investigators  emphasize  the  statement  that 
the  bacilli  are  prone  to  disappear  from  the  spots  after  from  three 
to  five  days,  and  that,  to  ensure  the  best  results,  the  exami- 
nations must  be  made  as  soon  as  possible  after  the  appearance  of 
the  roseola.  All  investigators  agree  that,  in  the  great  majority  of 
instances,  spot  cultures  give  positive  results  several  days  before 
the  appearance  of  the  serum  test.  The  chief  disadvantages  to 
this  method  of  diagnosis  appear  to  be  the  absence  of  the  roseola 
in  some  cases,  its  late  development  in  others,  and  the  possibility 
of  not  always  being  able  to  distinguish  typhoid  spots  from  other 
eruptions. 

The  technique  used  by  Richardson^  is  simple,  and  judging 
from  his  results,  trustworthy.  After  having  washed  the  skin  of 
the  part  with  alcohol  and  ether,  the  spot  is  frozen  with  an  ethyl- 
chloride  spray,  after  which  it  is  crucially  incised.      Its  substance 

1  Deut.  nied.  Woch.,  1895,  vol.  xxi.,  p.  550. 

^Centralbl.  f.  inn.  Med.,  1896,  vol.  xvii.,  p.  1249. 

3  John  Hopkins  Hosp.  Bull.,  1898,  vol.  ix.,  p,  54. 

*  Zeitschr.  f.  Hyg.,  1899,  vol.  xxx.,  p.  498. 

5  Miinch.  med.  Woch.,  1899,  vol.  xlvi.,  p.  1597. 

^Phila.  Med.  Journ.,  1900,  vol.  v.,  p.  514. 

"  Zeitschr.  f.  klin.  Med.,  1900,  vol.  xli.,  p.  405. 

^  Loc.  cit. 


ENTERIC    FEVER. 


319 


is  then  removed  by  scraping  with  a  small  skin-curette,  and  trans- 
ferred to  a  tube  of  nutrient  bouillon.  A  second  tube  is  inoculated 
with  the  blood  which  collects  as  soon  as  the  effects  of  freezing 
have  worn  off,  both  cultures  being  then  incubated  and  examined 
in  the  usual  manner.  At  least  five  or  six  spots  should  be  thus 
treated  in  each  case,  and  two  tubes,  one  for  the  scrapings,  the 
other  for  the  blood  inoculation,  used  for  each  spot. 

If  blood-serum  from  a  case  of  enteric  fever  is 
Serum  Test,  mixed  with  a  broth  culture  of  the  bacillus  typho- 
sus, and  a  small  drop  of  this  mixture  placed 
upon  a  slide  and  examined  under  the  microscope,  it  will  be  ob- 
served that  the  bacilli,  instead  of  continuing  to  dart  actively  to  and 
fro  across  the  field,  as  they  do  in  the  pure  culture,  are  attracted 
to  each  other,  lose  their  power  of  propulsion,  and  become  grouped 

Fig.  42. 


A    POSITIVE    REACTION. 

Large  clumps  of  motionless  bacilli  separated  by  open  spaces.     The  few  bacteria  outside  the  clumps 

are  devoid  of  motility. 

together  in  large  agglutinated  clumps  of  irregular  outline,  which, 
after  the  lapse  of  a  variable  length  of  time,  become  more  and 
more  compact  and  homogeneous.  In  the  typical  positive  reac- 
tion the  field  of  the  microscope  shows  islands  of  clumped  bacilli, 
separated  from  each  other  by  large  open  spaces,  containing  per- 
haps a  few  isolated  organisms  the  motility  of  which  is  decidedly 
inhibited  at  first,  and  finally  entirely  lost.  If  the  clumps  are  of 
very  large  size,  they  produce  a  peculiar  grayish  mottling  of  the 
specimen  visible  to  the  naked  eye,  a  point  to  which  attention 
was  first  directed  by  Greene.^     In  a  small   proportion  of  cases 

IN.  Y.  Med.  Record,  1896,  vol.  1.,  pp.  697  and  805. 


320  GENERAL    HEMATOLOGY. 

the  clumps  appear  to  undergo  a  granular  change,  and  then  be- 
come entirely  destroyed ;  in  some  instances  they  remain  un- 
altered for  several  days  ;  and  in  still  others  they  may  break  up 
after  a  few  hours,  the  field  then  becoming  refilled  with  isolated, 
actively  motile  bacteria. 

Fig.  43. 


A  PSEUDO-REACTION. 

A  few  small  clumps  of  bacilli  having  impaired  motility.    Persistent  motility  of  the  bacteria  in  other 

parts  of  the  field. 

In  a  certain  percentage  of  instances  the  agglutinated,  motion- 
less masses  of  bacilli  may  be  observed  as  soon  as  the  specimen  is 
brought  into  focus,  so  that  the  reaction  may  be  said  to  have 
taken  place  immediately.  In  other  instances  some  little  time 
elapses  before  the  character  of  the  test  can  be  determined,  and  in 
such  reactions  the  formation  of  the  clumps,  from  their  inception 
out  of  two  or  three  bacteria,  to  their  completion,  when  they  con- 
sist of  several  hundred  organisms  tightly  glued  together  into  a 
densely  crowded  mass,  may  be  studied  most  advantageously.  In 
these  slower  reactions,  while  early  clumping  may  progress  to 
some  extent,  many  isolated  bacteria  are  seen  the  motility  of 
which  persists  for  a  variable  period,  gradually  growing  less  and 
less,  until  finally,  with  more  or  less  crippled  powers  of  propulsion, 
the  organisms  are  attracted  to  the  clump  centers  with  which  they 
are  ultimately  incorporated,  either  becoming  adherent  at  first  ap- 
proach, or,  as  is  usually  the  case  with  the  more  active  bacilli, 
circling  around  the  edges  of  the  clump  for  some  little  time  before 
becoming  attached  to  it.  Still  other  reactions  are  characterized 
by  an  almost  immediate  cessation  of  motility,  followed  by  tardy 
agglutination,  and  usually  by  the  formation  of  clumps  of  smaller 
size  rthan  those  noted  in  a  prompt  and  immediate  reaction. 


ENTERIC    FEVER. 


321 


If  the  reaction  is  negative,  the  motility  of  the  bacilli  persists 
and  the  formation  of  clumps  is  not  observed,  regardless  of  the 
time  during  which  the  specimen  is  watched.  Not  unless  aggluti- 
nation is  marked  and  entire  loss  of  motility  occurs  may  a  reaction 
be  considered  positive ;  and  pseudo-reactions  resulting  in  the  for- 


FiG.  44. 


Bacillus  typhi  abdominalis. 
The  bacilli  are  actively  motile  throughout  the  field. 

mation  of  small  masses  of  more  or  less  motile  organisms,  together 
with  persistent  motility  of  many  unclumped  bacteria  in  other 
parts  of  the  field,  cannot  be  regarded  as  typical  in  any  sense. 
Clumping  of  small  numbers  of  bacteria  sometimes  occurs  in  the 
pure  culture  during  its  growth,  and  this  source  of  error  must  be 
eHminated  by  habitually  examining  the  culture  before  each  test 
or  series  of  tests. 

TecJiniqiic.  In  order  to  exclude  all  sources  of  error,  such  as 
may  arise  from  the  clumping  of  the  typhoid  bacillus  by  non- 
typhoid  serum,  provided  that  the  latter  is  sufficiently  concentrated 
and  is  allowed  enough  time  to  exert  its  agglutinative  powers,  the 
reaction  can  be  considered  of  diagnostic  value  only  under  the 
following  two  conditions  :  first,  that  the  blood  to  be  tested  must 
always  be  diluted  with  at  least  ten  volumes  of  the  culture  ;  and, 
second,  that  loss  of  motility  and  clump  formation  must  occur 
within  an  arbitrary  time  limit  of  thirty  minutes.  Under  these 
conditions  it  has  been  shown  that  agglutination  of  the  typhoid 
bacillus  is  produced  only  by  the  blood  from  a  patient  who  is  or 
who  has  been  infected  with  enteric  fever.  In  some  cases  of  ty- 
phoid the  reaction  occurs  in  much  higher  dilutions,  frequently 
with  dilutions  of  1 150,  or  i  :ioo,  or  even  higher.  Some  habitually 
21 


322  GENERAL    HEMATOLOGY. 

work  with  higher  dilutions  than  i:io,  but  they  extend  the  time 
limit  of  the  reaction  proportionately  to  the  degree  of  the  dilution 
used. 

Cultures  from  twelve  to  twenty-four  hours  old,  grown  in 
neutral  peptone-bouillon  from  a  stock  agar-agar  culture,  are  best 
adapted  for  the  test.  It  is  advisable  to  keep  all  the  cultures  at 
room  temperature,  and  to  transplant  the  stock  agar  growths  not 
oftener  than  once  a  month,  since  cultures  "forced"  by  incuba- 
tion and  by  frequent  transplanting  may  give  rise  to  false  reactions 
with  non-typhoid  blood.  The  cultures  should,  of  course,  be  ab- 
solutely uncontaminated,  and  must  respond  typically  to  the 
recosnized  tests  for  their  identification. 

The  test  may  be  conducted  either  microscopically,  by  the  dried 
blood  method,  or  by  the  use  of  fluid  blood,  or  fluid  serum  ;  or 
7nacroscopically,  the  method  preferred  by  Widal.^ 

The  dried  blood  method,  perfected  and  popularized  by  Wyatt 
Johnston,^  is  to  be  chosen  whenever  it  is  necessary  to  send  the 
blood  sample  any  distance  for  examination,  and  where  the  ex- 
aminer finds  it  inconvenient  to  carry  with  him  to  the  patient's 
bedside  the  test-tubes  required  for  the  methods  next  to  be  de- 
scribed. Johnston's  method  is  especially  adapted  for  use  by 
Health  Boards,  by  which  bodies  it  is  now  extensively  employed 
in  nearly  all  the  large  cities  in  this  country. 

The  technique  of  collecting  the  blood  specimens  is  exceedingly 
simple.  After  having  punctured  the  finger  or  ear  in  the  usual 
manner,  several  separate  drops  of  blood  are  collected  upon  the 
surface  of  some  non-absorbent  material,  preferably  glass,  then 
dried,  placed  in  an  envelope  or  other  protective  covering,  and 
tested  at  the  examiner's  convenience.  Glass  slides,  or  slips  of 
non-absorbent  Bristol  board  or  paper  are  most  commonly  used 
for  collecting  the  blood  samples,  and  specimens  thus  obtained 
may  be  kept  for  several  months  without  aseptic  precautions,  and 
still  retain  their  agglutinative  powers. 

If  the  specimen  has  been  collected  on  glass,  one  of  the  crusts 
is  moistened  with  a  drop  of  sterile  water  and  worked  up  into  a 
thin  paste  with  a  platinum  loop,  after  which  complete  solution 
and  proper  dilution  of  the  blood  is  effected  by  adding  nine  drops 
of  typhoid  bouillon  and  mixing  thoroughly.  If  the  sample  has 
been  dried  on  a  paper  or  cardboard  surface,  the  blood  crust  may 
be  cut  out  with  a  pair  of  scissors,  and  placed  to  soak,  face  down- 
ward, in  a  watch-glass  containing  ten  drops  of  the  culture. 

From  one  of  these  mixtures  of  blood  and  typhoid  culture  a 

^  Bull,  med.,  1896,  vol.  x.,  pp.  618  and  766. 
2N,  Y.  Med.  Journ.,  1896,  vol.  Ixiv.,  p.  57^. 


ENTERIC    FEVER. 


323 


minute  portion  is  transferred  to  the  center  of  a  clean  cover-glass, 
which  is  at  once  inverted  over  a  '*  concave  slide,"  sealed  with 
cedar-oil,  and  examined  as  a  hanging-drop  with  a  one-eighth- 
inch  dry  objective,  using  dim  illumination.  A  plain  glass  slip  is 
used  by  many  workers,  instead  of  a  "hollow-slide,"  but  either 
will  prove  satisfactory. 

If  the  fluid  blood  method  is  used,  the  dilution  is  made  at  the 
patient's  bedside,  by  adding  one  drop  of  the  whole  blood,  as  it 
flows  from  the  puncture,  to  ten  drops  of  typhoid  bouillon,  con- 
tained in  a  small  test-tube.  The  mouth  of  the  tube  is  then  closed 
by  a  cotton  plug,  and  its  contents  thoroughly  mixed  by  vigorous 
shaking.  At  the  time  of  the  test,  which  must  not  be  delayed 
more  than  a  few  hours  after  the  dilution  is  made,  a  small  drop  of 
the  mixture  is  removed  from  the  tube  and  examined  microscopic- 
ally in  the  usual  manner.  In  order  to  insure  accurate  dilutions, 
a  graduated  pipette  is  needed  for  measuring  the  blood  and  the 
culture,  for  the  drops  of  both  liquids  must  be  of  exactly  the  same 
size.  Either  the  special  pipettes  devised  for  serum  testing,  or  the 
Thoma-Zeiss  leucocytometer  will  prove  satisfactory  for  this  pur- 
pose. In  lieu  of  either  of  these  instruments  a  graduated  pipette 
may  be  readily  made  from  a  bit  of  glass  tubing,  or  an  ordinary 
medicine  dropper. 

If  the  liqiiid  serum  method  is  chosen,  fifteen  or  twenty  drops  of 
blood,  drawn  by  making  a  rather  deep  puncture,  are  allowed  to 
flow  into  a  narrow  calibered  test-tube,  and  set  aside  for  a  few 
minutes  until  coagulation  has  taken  place.  As  soon  as  the  clot 
has  formed,  the  nose  of  the  graduated  pipette  is  thrust  into  the 
test-tube,  and  one  drop  of  the  fluid  serum  sucked  up,  and  diluted 
with  ten  drops  of  typhoid  bouillon  contained  in  a  second  test-tube. 
The  preparation  for  microscopical  examination  is  then  made  from 
this  dilution.  If  the  requisite  apparatus  is  at  hand  the  serum  may 
be  obtained  by  centrifugalization. 

If  the  macroscopical  method  is  employed,  the  whole  procedure 
must  be  carried  out  under  the  strictest  aseptic  precautions,  for 
otherwise  the  growth  of  contaminating  bacteria  may  interfere  with 
the  reaction,  owing  to  the  length  of  time  required  for  the  comple- 
tion of  the  experiment. 

The  blood  from  which  the  serum  is  obtained  is  aspirated  from 
one  of  the  superficial  veins  of  the  arm,  according  to  the  technique 
employed  in  bacteriological  examinations,  and  then  immediately 
expelled  into  a  sterile  test-tube,  which  is  plugged  with  cotton,  and 
set  aside  until  clotting  occurs.  If  it  is  desired  to  send  the  speci- 
men any  distance,  the  blood  may  be  drawn  up  into  a  glass  bulb, 
previously  sterilized  by  heat,  and  then  sealed  at  both  ends.     Blood 


324  GENERAL    HEMATOLOGY. 

collected  in  this  manner  will  preserve  its  agglutinative  properties 
and  remain  sterile  indefinitely. 

Having  thus  obtained  the  serum  from  the  whole  blood,  the 
test  is  carried  out  by  adding  the  serum  in  definite  dilutions  to 
either  a  twenty-four-hour-old  bouillon  culture  of  the  typhoid 
bacillus,  or  to  sterile  bouillon  inoculated  with  a  typhoid  culture 
at  the  time  of  the  test. 

In  the  first  instance  a  1:10  dilution  of  serum  and  twenty-four- 
hour  typhoid  bouillon  is  made  in  a  sterile  test-tube,  which  is  then 
plugged,  and  placed  in  an  incubator,  where  it  remains  for  about 
twelve  hours,  at  a  temperature  of  37°  C.  At  the  expiration  of 
this  time  a  positive  reaction  may  be  recognized  by  the  presence 
of  dense,  whitish,  flaky  masses  (composed  of  large  clumps  of  ag- 
glutinated bacteria),  forming  in  the  typical  positive  reaction  a  thick 
precipitate  at  the  bottom  of  the  test-tube,  which  contrasts  with 
the  perfectly  clear  appearance  of  the  supernatant  bouillon.  If 
the  reaction  is  negativ^e,  the  tube  shows  simply  the  uniform  cloudi- 
ness of  an  ordinary  typhoid  bouillon  culture. 

In  the  second  instance  a  i:io  dilution  of  serum  and  sterile 
neutral  peptone  bouillon  is  made,  the  mixture  then  being  inocu- 
lated with  a  small  loopful  of  typhoid  bacilli  derived  either  from  a 
bouillon  or  an  agar  culture.  The  contents  of  the  test-tube  are 
then  thoroughly  mixed,  and  the  preparation  incubated  at  37° C, 
for  twenty-four  hours.  A  positive  reaction  is  characterized  after 
this  length  of  time  by  the  formation  of  a  similar  grayish-white 
precipitate  at  the  bottom  of  the  tube,  underlying  an  unclouded 
layer  of  fluid.  In  negative  reactions  the  typical  cloudiness  of  the 
typhoid  growth  is  diffused  throughout  the  bouillon. 

In  both  of  these  macroscopical  methods  control  tubes  of  normal 
serum  and  typhoid  bouillon  should  invariably  be  prepared,  and 
incubated  side  by  side  with  the  specimen  of  serum  to  be  tested. 

Both  tests  may  be  carried  out  at  ordinar}-  room  temperature, 
but  more  certain  and  more  typical  results  are  obtained  when  the 
tubes  are  incubated  at  a  temperature  of  37°  C. 

TJic  Choice  of  a  Method.  The  choice  between  the  four  methods 
of  serum  testing  described  above  must  depend  largely  upon  the 
circumstances  under  which  the  test  is  to  be  made. 

The  dried  blood  method,  as  already  remarked,  is  best  adapted 
to  Health  Board  necessities,  where  samples  of  blood  are  collected 
by  the  general  practitioner  and  sent  by  mail  to  the  laboratory. 
The  chief  objection  to  this  method  is  the  impossibility  in  many 
cases  of  making  accurate  dilutions,  since  usually  it  can  only  be  as- 
sumed that  a  given  crust  of  blood  represents  the  same  volume  in  its 
liquid  state  as  the  drop  of  culture  with  which  it  is  diluted.      If  the 


ENTERIC    FEVER.  325 

examiner  collects  the  specimens  himself,  quite  accurate  dilu- 
tions may  be  obtained  if  a  graduated  pipette  or  a  platinum  loop 
of  fixed  size  is  used  to  measure  both  the  blood  and  the  culture. 
Another  drawback  is  the  fact  that  more  or  less  typical  agglutina- 
tion occasionally  occurs  with  non-typhoid  blood,  although  John- 
ston believes  that  this  source  of  error  may  be  always  eliminated 
by  using  cultures  of  sufficient  attenuation. 

In  hospital  work  either  the  fluid  blood  or  fluid  serum  should 
be  chosen,  for  exact  dilutions  may  be  made  by  these  methods, 
and  if  the  test  is  made  within  a  reasonable  length  of  time  after  the 
dilution,  bacterial  contamination  need  not  be  feared.  The  writer, 
in  the  early  days  of  serum  testing  a  warm  advocate  of  Johnston's 
method,  has  now  discarded  it  wherever  possible  in  favor  of  the 
more  accurate  and  equally  simple  test  performed  with  the  fluid 
whole  blood,  or  serum. 

The  macroscopical  method  with  fluid  serum  is  too  slow,  and 
requires  too  elaborate  bacteriological  apparatus  ever  to  be  adopted 
for  general  clinical  use.  At  present  it  is  chiefly  used  by  a  few 
British  and  Continental  observers  in  experimental  work,  but  has 
not  found  popularity  in  this  country. 

Value  of  the  Serum  Test.  Fully  95  per  cent,  of  all  typhoids  give 
a  positive  reaction  at  some  period  of  the  disease,  usually  as  early 
as  the  eighth  day,  as  nearly  as  it  is  possible  to  compute  this  period. 
An  error  of  about  3  per  cent,  must  be  allowed  for,  on  account  of 
the  occurrence  of  positive  or  misleading  results  with  non-typhoid 
blood.  The  statistics  of  the  Philadelphia  Bureau  of  Health  are 
of  interest  in  demonstrating  the  usefulness  of  the  test  in  routine 
public  health  work.  The  report  for  1898^  shows  that  5,293 
specimens  from  4,597  cases  diagnosed  enteric  fever  were  tested 
by  the  dried  blood  method,  with  a  discrepancy  of  5  per  cent,  be- 
tween the  laboratory  and  the  clinical  diagnosis  ;  while  the  report 
for  1899^  shows  that  the  discrepancy  was  only  3.9  per  cent., 
based  on  the  examination  of  5,350  samples  of  blood  from  4,483 
suspected  cases.  In  1900^  3^205  specimens  from  2,745  suspected 
cases  were  examined,  with  a  discrepancy  of  7.  i  per  cent,  between 
the  clinical  and  the  laboratory  findings. 

In  some  instances  repeated  negative  results  are  found  until  con- 
valescence is  well  established,  and,  rarely,  cases  are  encountered 
in  which  the  reaction  never  occurs  at  any  time  during  the  entire 
course  of  the  illness.     The  blood  may  lose  its  clumping  powers 

1  A.  C.  Abbott :  Annual  Report  of  the  Division  of  Bacteriology,  Pathology,  and 
Disinfection  of  the  Philadelphia  Bureau  of  Health,  1899,  p.  199. 

2  Ibid.,  1900,  p.  92. 
3 Ibid.,  1901,  p.  107. 


326  GENERAL    HEMATOLOGY. 

at  about  the  time  of  defen^escence,  or,  on  the  other  hand,  this  pe- 
cuHarity  may  persist  for  months,  or  even  years  after  the  attack. 
This  last  source  of  error  in  the  test  may  be  due  to  the  presence 
of  unsuspected  foci  containing  typhoid  bacilH,  but  sometimes  it 
is  apparently  independent  of  such  factors.  Before  pronouncing 
upon  the  value  of  a  positive  reaction  in  the  individual  case,  the 
occurrence  of  a  previous  attack  of  typhoid,  and  the  presence  of 
lesions  which  may  be  due  to  the  Ebeith  bacillus  (osteomyelitis, 
cystitis,  arthritis,  cholecystitis,  etc.)  must  be  excluded. 

The  reaction  may  be  positive  on  one  day  of  the  disease  or  for 
a  series  of  days,  and  negative  on  the  next  day  or  succeeding  days. 
Its  character  is  apparently  uninfluenced  by  the  intensity  of  the 
infection,  for  although  as  a  rule  the  reaction  is  usually  prompt 
and  marked  in  severe  infections,  it  maybe  just  as  marked  in  mild 
cases.  A  certain  relationship  seems  to  exist  between  the  height 
of  the  fever  and  the  intensity  of  the  reaction,  for  the  latter  is 
usually  most  decided  at  the  period  of  maximum  pyrexia. 

In  the  light  of  our  present  knowledge  of  the  serum  test,  its 
value  appears  to  be  less  than  its  first  enthusiastic  advocates  were 
inclined  to  urge.  A  positive  reaction,  obtained  by  a  skilled 
worker  whose  technique  as  to  dilution,  time  limit,  and  culture  has 
been  exact,  is  the  most  valuable  single  sign  of  enteric  fever,  al- 
though it  cannot  be  regarded  as  absolutely  pathognomonic.  On 
the  other  hand,  a  negative  result  with  the  test  is  no  proof  of 
the  absence  of  the  disease. 

Anemia  develops  shortly  after  the  beginning 
Hemoglobin    of  the  fever,  slowly  and  progre.ssively  increasing 
AND  in  intensity  throughout  the  course  of  the  disease, 

Erythrocytes,  and  persisting  during  the  early  weeks  of  defer- 
vescence. During  the  first  week  there  is  little  or 
no  decrease  in  the  number  of  erythrocytes,  although  the  hemo- 
globin loss  appears  to  begin  coincidentally  with  the  first  manifes- 
tations of  the  infection.  Normal  er}'throcyte  counts  are  the  rule 
during  the  first  seven  days,  but  there  are  few  cases  of  typhoid 
which  fail  to  show  a  hemoglobin  loss  amounting  to  at  least  1 5 
or  20  per  cent,  during  this  period.  Whether  this  early  oligo- 
chromemia  is  due  to  the  influence  of  the  fever,  or  whether  it  rep- 
resents the  actual  prefebrile  state  of  the  patient's  blood,  is  difficult 
to  decide.  By  the  second  week  the  corpuscular  decrease  be- 
comes evident  and  steadily  grows  more  and  more  marked  as  the 
disease  progresses,  reaching  its  maximum  at  about  the  end  of  de- 
fer\^escence.  Thayer  ^  distinguishes  a  slight  accentuation  of  the 
oligocythemia  between  the  third  and  fourth  weeks,  the  decrease 

1  Johns  Hopkins  Hosp.  Reports,  190O,  vol.  viii.,  p.  487. 


ENTERIC    FEVER. 


327 


continuing  until  the  seventh,  when  a  still  more  decided  fall  occurs, 
followed  in  the  eighth  week  by  a  considerable  rise.  A  slow  rise 
in  the  erythrocyte  curve  is  observed  after  defervescence,  and,  in- 
deed, sometimes  before  the  end  of  the  febrile  stage,  until  by  the 
end  of  the  fourth  or  fifth  week  of  convalescence  the  count  is 
again  normal.  The  hemoglobin,  after  the  first  week,  follows  the 
same  general  course  as  the  erythrocytes,  but  its  decrease  during 
the  early  weeks  is  relatively  greater  and  its  regeneration  slower 
during  the  post-febrile  period. 

Thayer's  analysis  ^  of  the  blood  examinations  in  enteric  fever, 
made  in  the  Johns  Hopkins  Hospital  during  the  past  eleven  years, 
furnishes  a  striking  illustration  of  the  development  of  the  anemia 
during  the  progress  of  the  disease.  Arranged  according  to  the 
week  of  the  fever,  the  following  hemoglobin  and  erythrocyte 
averages  in  uncomplicated  cases  are  shown  : 


Hemoglobin. 
(165  estimates.) 

1st  week,  2i  estimates,  76.1  per  cent.  6th  week,  6  estimates,  62,1  per  cent. 

72.8       "  7th      "      4         "         50.5       " 

66.2       "  8th      "      3         "         56.9       *' 

60.5       "  9th      "     4         ''         47.7       " 


2d 

<< 

51 

3d 

(( 

34 

4th 

( < 

20 

5th 

(( 

20 

57-8 


loth 


66.5 


Erythrocytes. 

(265  counts.) 

1st  week,  32  counts,  4,913,312  7th  week,  8  counts,  3,309,125 


2d 

3d 
4th 
5th 
6th 


86 

59 
36 
22 

7 


4,692,428 
4,429,208 
4,222,236 
4,118,590 
4,028,428 


8th 

9th 

loth 

nth 


3,652,285 
3,509.966 
3,920,000 
2,109,333 


Seventy-four  typhoid  patients,  both  with  and  without  compli- 
cations, examined  in  the  German  and  the  Jefferson  Hospitals, 
show  the  following  averages,  the  first  estimates  being  taken  in  all 
cases  in  which  multiple  examinations  were  made  : 


Week. 

Hemoglobin. 

Erythrocytes. 

I  St  week, 

14 

cases. 

77.4  per  cent. 

4,789,285 

per  cb.  mm 

2d 

30 

66.5 

4,161,233 

3d 

13 

58.8 

3,555,000 

4th 

6 

49.6 

3,490,833 

5th 

6 

t  ( I 

53-1 

2,445,000 

6th 

2 

47-5 

3,165,000 

7th 

2 

47.5 

3,335.000 

8th 

I 

40.0 

2,790,000 

1  Loc.  cit. 


328  GENERAL    HEMATOLOGY. 

As  a  rule,  the  degree  of  a  typhoid  anemia  is  parallel  to  the 
severity  of  the  attack,  but  this  is  not  invariably  true,  since  a 
mild  case  may  be  associated  with  a  most  intense  anemia.  In 
the  series  included  in  the  last  tabulation  the  most  marked  instances 
of  anemia  showed  hemoglobin  and  erythrocyte  estimates  of  40 
per  cent,  and  1,720,000,  40  per  cent,  and  1,850,000,  and  50  per 
cent,  and  1,800,000,  respectively.  The  most  striking  example  of 
oligochromemia  showed  a  hemoglobin  percentage  of  20,  with  a 
corresponding  erythrocyte  count  of  2,470,000.  Considerably 
lower  estimates  than  these  have  been  reported  by  a  number  of 
other  observers,  but  they  are  uncommon. 

The  effects  of  the  cold  tub,  and  of  excessive  diarrhea  and 
sweating  may  cause  a  temporary  polycythemia  from  concentra- 
tion of  the  blood,  and  these  sources  of  high  counts  must  be  ex- 
cluded in  making  examinations  during  the  early  weeks  of  the 
disease.  In  four  cases  examined  by  the  writer  to  determine  the 
effects  of  the  cold  plunge,  it  was  found  that  the  average  eiy- 
throcyte  increase  after  the  bath  amounted  to  813,000  corpuscles 
per  cubic  millimeter,  and  the  hemoglobin  gain  to  8  per  cent. 
Hemorrhages,  if  severe,  may  cause  an  abrupt  fall  in  the  erythro- 
cyte count,  often  succeeded  by  a  more  or  less  successful  attempt 
at  regeneration,  in  an  effort  to  compensate  for  the  blood  loss. 

Qualitatively,  the  cells  show  no  peculiar  changes,  poikilocytosis, 
irregular  staining  affinities,  and  deformities  of  size  occurring  in 
relation  to  the  intensity  of  the  anemia.  Erythroblasts  are  com- 
paratively rare,  being  absent  or  few  in  number  in  the  average  case. 
Normoblasts  may  be  found  in  cases  with  high-grade  anemia,  and 
as  a  sequel  to  hemorrhage.  Megaloblasts  are  very  rare,  an  oc- 
casional cell  of  this  type  being  observed  now  and  then  only  in 
severe  cases. 

'•  A  steady,  slow  decrease  in  the  number  of  leu- 

Leucocytes.  cocytes  becomes  evident  after  the  first  week  of  the 
fever,  the  lowest  counts  being  found  during  the 
fifth  or  sixth  week,  after  which  an  increase,  which  may  be  either 
permanent,  or  transient  and  followed  by  a  still  more  decided 
leucopenia,  is  observed.  It  appears  that  the  latter  change  ac- 
companies cases  with  severe  post-febrile  anemia,  although  suf- 
ficient data  are  lacking  to  justify  absolutely  positive  conclusions 
on  this  point.  In  uncomplicated  cases  the  normal  count  becomes 
reestablished  by  about  the  fourth  week  of  convalescence.  The 
leucopenia  of  typhoid  corresponds  in  a  general  way  to  the  severity 
of  the  attack,  and  although  not  marked  in  the  average,  in  the 
individual  case  it  may  be  striking,  counts  of  from  2,000  to  3,000 
being  not  at  all  uncommon. 


ENTERIC    FEVER. 


329 


Thayer's  report  of  832  counts  in  uncomplicated  cases  shows 
the  following  range  of  the  leucocytes,  according  to  the  week  of 
the  disease  : 


I  St  week,  119  counts,  6,442, 


8th  week,  14  counts,  6,614 


2d     '* 

258       ' 

'        6,251, 

9th 

7 

'       5,057 

3d     '' 

200       * 

'        5,528, 

loth 

2        ' 

'       5,000 

4th    '' 

117       ' 

5,431, 

nth 

3 

'       5,333 

5th    - 

70       ' 

5,510, 

1 2th 

2        ' 

'       5,000 

6th    '' 

25       ' 

5,690, 

13th 

I        * 

^       8,000 

7th    '' 

14       ' 

6,132. 

The  leucocyte  estimates  of  the  74  hospital  typhoids  referred  to 
above  averaged  : 

ist  week,  14  cases,  8,026  leucocytes  per  cb.  mm. 


2d           ' 

'      30 

6,713 

C<                  (( 

3d       ' 

'      13 

7,076 

(             il 

4th      ' 

6 

4,400 

i           (( 

5th      ' 

6 

5,766 

(                IC 

6th      ' 

*        2 

6,250 

I           (( 

7th      ' 

*        2 

4,500 

I           (( 

8th      ' 

'        I 

8,000 

(           (( 

Disregarding  the  week  of  the  fever,  the  number  of  leucocytes 
in  these  cases  ranged  as  follows  : 


Above 

10,000                 in 

7 

cases 

From 

9,000-10,000  " 

3 

8,000-  9,000  " 

8 

7,000-  8,000  " 

14 

6,000-  7,000  " 

8 

5,000-  6,000  " 

10 

4,000-  5,000  " 

II 

3,000-  4,000  '' 

8 

2,000-  3,000  " 

4 

1,000-  2,000  *' 

I 

Highest:    16,000  per  cb.  mm. 

Lowest:     1,333      " 

<  ( 

Average  :  6,706      '* 

(( 

It  appears  from  these  figures  that  counts  in  excess  of  10,000 
per  cubic  millimeter  may  be  looked  for  in  more  than  10  per 
cent,  of  all  cases,  such  an  increase  being  due  either  to  the  effects 
of  blood  concentration  from  diarrhea,  sweating,  vomiting,  or  cold 
tubbing,  or  to  some  hidden  or  frank  complication.  In  4  of  the 
7  relatively  high  counts  above  noted,  the  cause  was  plain — 
croupous  pneumonia  in  2,  cholecystitis  in  i,  and  furunculosis  in 


330  GENERAL    HEMATOLOGY. 

I.  In  the  other  3,  all  of  which  were  made  in  patients  whose 
fever  had  not  yet  run  seven  days,  the  factors  of  the  increase  were 
undetermined  ;  possibly  it  was  due  to  physiological  blood  in- 
spissation. 

Inflammatory  complications,  such  as  otitis,  abscess,  pneumonia, 
severe  bronchitis,  peritonitis,  cystitis,  periostitis,  and  phlebitis  give 
rise  to  a  prompt  leucocytosis  in  patients  whose  vital  powers  are 
sufficiently  strong  to  react  against  the  process.  Intestinal  hemor- 
rhage is  usually  followed  by  an  increase  reaching  its  maximum 
within  twenty-four  hours  after  the  blood  loss,  and  disappearing 
within  a  week.  Intestinal  perforation  may  be  promptly  followed 
by  a  leucocytosis,  the  increase  developing  within  a  few  hours. 
Thayer  has  observed  that  in  some  instances  the  increase  in  the 
number  of  leucocytes  succeeding  the  perforation  may  tend  to 
diminish  and  disappear  with  the  aggravation  of  the  symptoms, 
and  that  not  infrequently  there  is  a  complete  absence  of  leucocy- 
tosis and  sometimes  a  diminution  in  the  number  of  leucocytes 
after  this  accident.  He  also  considers  that  the  prospect  of  reUef 
by  surgical  interference  is  best  in  those  cases  with  a  leucocytosis, 
the  absence  or  disappearance  of  this  sign  following  a  perforation 
being  an  indication  of  the  malignancy  of  the  infection  or  the  pros- 
tration of  the  patient. 

Qualitative  changes  are  absent  or  inconspicuous  during  the 
first  two  weeks  of  the  fe\'er,  but  during  the  third  week  a  slow, 
progressive  decrease  in  the  relative  percentage  of  polynuclear 
neutrophils,  with  a  consequent  increase  in  the  mononuclear  un- 
granulated  forms,  begins,  this  change  becoming  most  marked  at 
about  the  end  of  defervescence.  In  23  of  the  writer's  cases  the 
percentage  of  polynuclears  averaged,  according  to  the  week  of 
the  disease,  75.0  per  cent,  for  8  cases  in  the  first  week;  70.9 
per  cent,  for  7  in  the  second  week  ;  50.2  for  4  in  the  third  week ; 
60.0  per  cent,  for  2  in  the  fourth  week  ;  and  64.0  and  68.0  per 
cent,  for  a  single  case  in  the  fifth  and  sixth  weeks,  respectively. 

Thayer  has  found  that  the  mononuclear  cells  which  are  most 
markedly  increased  are  "  elements  containing  nuclei  not  much 
larger  than  those  of  lymphocytes,  and  often  presenting  the  gen- 
eral appearance  of  a  lymphocyte  nucleus,  with  the  exception  of 
the  slight  affinity  for  coloring  matters.  The  size  of  these  cells  is 
usually  about  that,  or  but  little  larger  than  that  of  the  ordinary 
polymorphonuclear  neutrophile."  The  typical  small  lymphocyte, 
and  the  "transitional  "  forms  undergo  little  or  no  increase. 

The  eosinophils  are  almost  invariably  decreased,  both  abso- 
lutely and  relatively,  and  are  often  absent  during  the  active 
febrile  stages.     The   relative  percentages  of  these  cells   in  the 


ENTERIC    FEVER. 


331 


above  cases  averaged  0.87,  rising  as  high  as  5  per  cent,  in  only 
2  cases,  and  being  entirely  absent  in  1 1 . 

Myelocytes  in  small  numbers  may  be  found  in  severe  forms 
of  post-typhoid  anemia,  but  they  are  absent  during  the  active 
period  of  the  infection.  Tiirk's  ''stimulation  forms"  are  met 
with  under  the  same  conditions. 

Thayer's  elaborate  report  of  the  Johns  Hopkins  Hospital  cases 
includes  the  following  averages  of  the  differential  leucocyte  counts  : 


Week. 

Small  Mono- 

Large Mono- 

Polynuclear 

Eosinophile. 

nuclear. 

nuclear 

Neutrophile. 

1st  week,  12  counts. 

12.9% 

12.4% 

74-o% 

0.5% 

2d       '*       39       " 

14.6 

13-4 

70.9 

0.8 

3d       "      34       '' 

21.5 

II. 6 

66.3 

03 

4th     **       19       '* 

20.1 

14.4 

65.0 

0.4 

5th     "        8      " 

18.2 

19.7 

61.7 

0.3 

6th     "        4      " 

22.6 

135 

57-7 

6.0 

7th     "        I       '* 

23-7 

34-4 

37-3 

4.6 

8th     "        I       " 

24.2 

16.8 

56.9 

2.1 

According  to  Hayem,^  the  number  of  blood  plaques  is  markedly 
■decreased  during  the  febrile  period  of  the  fever,  as  in  any  other 
condition  characterized  by  pyrexia. 

The  blood  examination  furnishes  three  clinical 

Diagnosis,  signs  of  positive  value  in  the  diagnosis  of  enteric 
fever :  the  serum  reaction  ;  a  subnormal  leuco- 
cyte count  or  at  least  an  absence  of  leucocytosis  ;  and  in  cases 
with  roseola  the  detection  of  the  Eberth  bacillus  by  spot  cultur- 
ing.  The  influence  of  complications  upon  the  behavior  of  the 
leucocytes  must,  however,  always  be  borne  in  mind. 

Malarial  fever,  acute  miliary  tuberculosis,  cerebrospinal  menin- 
gitis, certain  atypical  cases  of  pneumo7iia  and  influenza,  and  septi- 
cemic and  pyemic  processes,  such  as  ulcerative  endocarditis,  are 
the  diseases  most  frequently  confounded  with  typhoid,  and  in  their 
differentiation  the  blood  report  often  gives  just  the  essential  clue. 

Malarial  and  enteric  fevers  are  both  associated  with  an  absence 
of  leucocytosis,  but  in  the  former  the  presence  in  the  blood  of  the 
malarial  parasite  and  pigment  is  sufficiently  conclusive.  Acute 
miliary  tuberculosis,  if  a  pure  infection,  also  shows  a  similar 
absence  of  a  leucocyte  increase,  and  in  excluding  this  disease 
reliance  must  be  placed  on  the  Widal  test ;  should  this  prove  nega- 
tive, attempts  may  be  made  to  culture  specific  bacteria  from  the 
blood.  Influenza  is  not  characterized  by  leucocytosis,  and  must  be 
differentiated  from  typhoid  by  the  aid  of  the  serum  test.      Cerebro- 


1  *'Du  Sang,"  etc.,  Paris,  1889. 


332  GENERAL    HEMATOLOGY. 

Spinal  meningitis,  pneumonia,  and  septic  and  pyemic  conditions 
may  be  differentiated  by  their  association  with  a  more  or  less 
well-marked  leucocytosis.  In  the  last-named  processes  bacterio- 
logical examination  of  the  blood  not  infrequently  gives  conclusive 
results. 

XVII.     ERYSIPELAS. 

In  severe    infections  Tiirk^  has  noted    a  de- 
Gexeral       cided  increase  in  the  quantity  oi  fibrin  and  in  the 
Features.      number  of  blood  plaques,  but  in  the  case  of  average 
severity  these  changes  are  not  to  be  observed. 
Drouin  ^  has  found  that  the  alkalinity  of  the  blood  is  greatly  de- 
creased.     Negative  results  from  bacteriological  examination  of  the 
blood  are  the  rule. 

Moderate  anemia,   characterized  bv  a   some- 
Hemoglobin    what  disproportionate  hemoglobin  loss,  is  com- 
and  mon  in  the  severer  forms  of  the  disease,  but  not 

Erythrocytes,  in  mild  cases.  The  decreases  are  not  notable, 
amounting  on  the  average  to  a  loss  of  not  more 
than  10  or  20  per  cent,  of  corpuscles  and  of  about  30  per  cent, 
of  hemoglobin.  Maragliano's  degenerative  changes  of  corpus- 
cular structure  have  occasionally  been  found. 

Leucocytosis  of  the  polynuclear  neutrophile 
Leucocytes,  type  is  the  usual  finding,  but  mild  cases  fre- 
quently run  their  course  without  provoking  the 
slightest  increase.  Except  in  isolated  instances,  the  leucocytosis 
is  not  high,  the  counts  usually  being  about  15,000,  and  rarely 
more  than  20,000  cells  to  the  cubic  millimeter.  Von  Limbeck,^ 
and  Chantemesse  and  Rey  ^  have  shown  that  the  leucocyte  and 
temperature  curves  maintain  a  definite  parallelism  in  the  majority 
of  cases,  and  that  the  diminution  in  the  leucocytosis  as  a  rule 
anticipates  the  fall  in  temperature.  There  is,  however,  no  appa- 
rent relationship  between  the  height  of  the  leucocytosis  and  the 
degree  of  pyrexia,  for  moderate  leucocytoses  are  not  incompatible 
with  strikingly  high  temperatures.  It  is  generally  agreed  that 
the  highest  counts  are  found  in  the  severest  cases,  provided  that 
the  patient's  resisting  powers  are  acting  normally.  An  exten- 
sion of  the  lesion  is  generally  accompanied  by  an  increase  in 
the  leucocytosis. 

With  the  onset  of  convalescence,  as  the  leucocytosis  disappears 
the  normal  percentages  of  the  different  forms  of  leucocytes,  dis- 

'  Loc.  cit. 

2  These  de  Paris,  1892,  n.  ^t^,  p.  108. 

3  Loc.  cit. 

*Presse  med.,  1899,  vol.  vi.,  p.  316. 


FEVER.  333 

turbed  during  the  febrile  period,  are  reestablished  by  a  rapid 
increase  in  the  small  lymphocytes  and  eosinophiles,  and  a  decrease 
in  the  polynuclear  neutrophiles  ;  the  percentage  of  large  lympho- 
cytes remains  stationary,  and  the  eosinophiles  are  absent  during 
the  height  of  the  attack,  according  to  Chantemesse  and  Rey. 
Small  percentages  of  myelocytes  and  an  occasional  "stimulation 
form"  are  commonly  found  during  the  active  stages  of  the  leuco- 
cytosis. 

XVIII.     EXOPHTHALMIC    GOITRE. 

There  are  no  characteristic  changes  in  the  hemoglobin  and 
erythrocytes,  although  an  anemia  indistinguishable  from  typical 
chlorosis  is  not  an  infrequent  feature.  Such  cases  must  be  dis- 
tinguished from  so-called  ''thyroid  chlorosis,"  or  chlorosis  with 
thyroid  hypertrophy,  by  means  of  other  clinical  symptoms.  It 
seems  likely  that  in  cases  of  Grave's  disease  characterized  by 
excessive  diaphoresis,  emesis,  and  diarrhea,  the  blood  concen- 
tration thus  produced  may  be  sufficient  more  or  less  effectually 
to  obscure  the  real  grade  of  anemia  existing. 

The  leucocytes  are  not  increased  in  number,  and  leucopenia  of 
a  decided  degree  is  frequently  observed.  Relative  lymphocytosis 
is  a  common  change,  and  moderate  increase  in  the  percentage  of 
eosinophiles  an  occasional  finding. 

XIX.     FEVER. 

It  is  a  well-recognized  fact  that  more  or  less  he^noglobin  and 
erythrocyte  losses  follow  pyrexia  maintained  for  any  length  of 
time,  but  an  attempt  to  demonstrate  the  exact  cause  or  group  of 
causes  of  this  anemia  involves  the  analysis  of  a  most  complex 
problem  in  physiology,  about  which  the  most  skilled  investigators 
express  diametrically  opposite  opinions.  Some  maintain  that  suffi- 
cient actual  destruction  of  the  corpuscles  occurs  as  the  result  of 
fever  to  account  for  their  decrease  in  number,  while  others  attrib- 
ute the  loss  largely,  if  not  wholly,  to  the  influence  of  vasomotor 
changes.  Maragliano  ^  has  shown  that  capillary  contraction  ac- 
companies the  period  of  active  pyrexia,  while  Reinert  ^  suggests 
that  the  blood  is  diminished  in  volume  by  the  excessive  drain 
upon  the  body  fluids  occurring  at  this  time.  In  septic  fevers, 
furthermore,  additional  inspissation  of  the  blood  is  produced  by 
the  influence  of  bacteria  and  their  products.  These  factors  tend- 
ing to  inspissate  the  blood  favor  the  production  of  polycythemia, 
which  change  is  to  be  observed  during  the  stage  of  active  fever. 
But  as  defervescence  sets  in  the  conditions  are  reversed,  for  the 

1  Berl.  klin.  Woch.,  i887,vol.  xxiv  ,  p.  797. 

2**  Die  Zahlung  der  roten  Blutkorperchen."     Lepzig,  1891. 


334  GENERAL    HEMATOLOGY. 

capillaries  then  dilate,  the  draining  away  of  the  fluid  elements  of 
the  blood  ceases,  and,  consequently,  dilution  of  the  blood  now 
occurs.  Anemia  therefore  develops  coincidentally  with  the  dis- 
appearance of  the  fever.  It  is  undetermined  whether  this  post- 
febrile anemia  is  the  result  purely  of  these  physical  causes,  or  of 
these  causes  plus  a  certain  amount  of  real  hematocytolysis  due 
to  high  temperature.  It  seems  reasonable  to  regard  both  factors 
as  active. 

Coagulation  and  fibrin  behave  so  erratically  that  no  definite 
statements  regarding  them  are  justified.  In  the  incipient  stage 
of  septic  fevers  coagulation  is  much  delayed,  according  to 
Schmidt,^  but  during  the  later  stage  it  occurs  more  rapidly  than 
normal.  The  leucocytes  in  this  class  of  fevers  are  generally 
increased  in  number. 

The  alkalinity  of  the  blood  undergoes  wide  variations  in  differ- 
ent febrile  states,  but  it  cannot  be  said  that  these  changes,  which 
are  probably  due  to  complex  chemical  processes  rather  than  to 
the  primary  effect  of  the  fever,  are  constantly  parallel,  either  to 
the  degree  of  pyrexia  or  to  the  behavior  of  the  leucocytes. 
Lowy  and  Richter^  state  that  increased  alkalinity  occurs  co- 
incidentally with  the  stage  of  hypoleucocytosis — a  statement 
which  Strauss,^  Lowit,^  and  others  have  verified.  Fodor  and 
Rigler's  experiments^  have  proved  that  the  pyrexia  following 
infection  with  pathogenic  bacteria  ultimately  effects  a  diminution 
in  the  alkalinity  of  the  blood,  and  that  this  change  is  sometimes 
preceded  by  a  distinct  primar}^  increase.  The  conclusions  voiced 
by  von  Jaksch,^  Kraus,''  and  other  earlier  wTiters,  that  decreased 
alkalinity  is  a  constant  accompaniment  of  febrile  processes,  can- 
not be  unreservedly  accepted  if  von  Limbeck's  ^  later  statements 
to  the  contrary  are  to  be  believed. 

XX.     FILARIASIS. 

Filariasis,  the  pathological  condition  depend- 

OccuRRENCE.    ing  upon  the  presence  in  the  body  of  the  parental 

and    embryonic    forms  of  the  filaria  sangninis 

hominis,  is  of  widespread  distribution  throughout  the  tropics  and 

subtropics,  being  prevalent  in  various  districts  of  Africa,  India, 

'  Pfliiger's  Archiv.,  1875,  vol.  xi.,  pp.  291  and  515. 
2Deut.  med.  Woch.,  1895,  vol.  xxi.,  p.  526. 
'Zeitschr.  f.  klin.  Med.,  1896,  vol.  xxx.,  p.  315. 
*"Die  Lehre  v.  Fieber,"  Jena,  1897. 
^Centralbl.  f.  Bakt.  u.  Infect.,  1897,  vol.  xxi.,  p.  134. 
^Zeitschr.  f.  klin.  Med.,  1887,  vol,  xiii.,  p.  380. 
'Zeitschr.  f.  Heilk.,  1889,  vol.  x.,  p.  106. 
sCentralbl.  f.  inn,  Med.,  1895,  vol.  xvi.,  p.  649. 


FILARIASIS.  335 

Australia,  China,  Japan,  South  America,  and  the  islands  of  the 
South  Pacific  and  the  West  Indies,  and,  as  mentioned  below,  hav- 
ing been  found  to  a  limited  extent  in  North  America. 

Six  distinct  species  of  embryo  blood  worms, 
Parasitology,  the  parental  forms  of  which  do  not  enter  the  cir- 
culation, have  been  demonstrated  in  the  periph- 
eral blood  of  man,  these  parasites  being  known  by  the  general 
term,  filaria  sanguinis  hominis.  These  different  filariae,  according 
to  the  nomenclature  suggested  by  Manson,^  are  distinguished  by 
the  r\diVC\QS  filaria  nocturnal  filaria  diurna,  filaria  per stans,  filaria 
Demarquaii,  filaria  Ozzardi^  and  filaria  Magalhdesi.  To  but  a 
single  member  of  this  group,  the  filaria  nocturna^  has  an  undis- 
puted pathological  role  been  assigned,  this  parasite  being  regarded 
as  the  cause  of  various  forms  of  lymphangitis,  of  lymph  varices, 
of  lymph  scrotum,  of  tropical  elephantiasis  Arabum,  of  endemic 
chyluria,  of  chylous  ascites,  and  of  other  tropical  diseases  of  more 
or  less  obscure  nature.  The  filaria  pcrstans,  Manson  conjectures, 
may  possibly  be  the  etiological  factor  of  that  peculiar  West  African 
disease  known  as  negro  lethargy,  or  the  **  sleeping  sickness  "  of 
the  Congo,  as  well  as  of  a  form  of  African  kra-kra,  or  *'  craw- 
craw."  Further  study  of  this  subject  is  necessary,  however,  be- 
fore these  relationships  may  be  unreservedly  credited.  The  other 
filariae  {diiirna,  Deniai'quaii,  Oszardi  and  Magalhdesi )  possess  no 
interest  from  a  diagnostic  standpoint,  since  their  life  history  and 
pathological  significance  are  still  obscure.^ 

This  is  by  far  the  most  important  member  of 

The  Filaria  the  above-named  class  of  blood  worms,  being  the 

NocTURNA.     one  most  familiarly  known  of  all,  as  well  as  the 

one  of  greatest  clinical  interest,  because  of  the 

interesting  pathological   lesions  which  it  is  capable  of  exciting. 

In  this  country  cases  of  filariasis  due  to  \h^  filaria  noctiirjia  have 

been  reported  by  a  number  of  different  observers,  Guiteras,^  de 

Saussure,^  Mastin,^  Slaughter,"  F.  P.  Henry,^  Dunn,^  and  Lothrop 

»" Tropical  Diseases,"  N.  Y.,  1898. 

2  The  author  is  greatly  indebted  to  Dr.  F.  P.  Henry  and  to  Dr.  J.  H.  Gibbon  for 
the  opportunity  of  making  repeated  blood  examinations  in  two  cases  oi  filaria  noc- 
turna  infection  occurring  in  their  respective  hospital  services. 

3  For  a  complete  description  of  filariasis  and  of  the  various  forms  of  the  filariae  the 
reader  should  consult  Manson' s  article  in  Davidson's  "  Hygiene  and  Diseases  of  the 
Warm  Climates"  (Edinburgh,  1893),  or  this  author's  text-book  to  which  reference  is 
made  above. 

*Med.  News,  1886,  vol.  xlviii.,  p.  399. 

5  Med.  News,  1890,  vol.  Ivi.,  p.  704. 

6  Annals  of  Surg.,  1888,  vol.  viii.,  p.  321. 
^Med.  News,  1891,  vol.  ii.,  p.  649. 

8  Med.  News,  1896,  vol.  xviii.,  p.  477. 

9  Trans.  Coll.  of  Phys.  of  Phila.,  1898,  p.  80. 


336  GENERAL    HEMATOLOGY. 

and  Pratt/  having  met  with  the  disease.  A  few  of  these  cases 
have  been  regarded  by  their  reporters  as  indigenous,  but  the 
great  majorit>'  of  them,  it  is  safe  to  state,  were  directly  imported 
from  the  tropics.  To  the  writer's  knowledge,  at  least  three  cases 
have  been  diagnosed  in  Philadelphia  during  the  last  four  years. 

Fig.  45. 


:\ 


'i'.^ 


The  filaria  nocturna. 
From  a  photomicrograph  of  the  parasite  in  fresh  blood. 

As  may  be  inferred  from  the  name,  the  embryos  of  Xh^  filaria 
nocturna  are  found  in  the  peripheral  blood  most  abundantly  at 
night,  the  vast  majority  of  the  parasites  retiring  into  the  deeper 
circulation  during  the  daytime.  From  late  in  the  afternoon 
until  about  midnight  they  make  their  way  into  the  peripheral 
vessels  in  progressively  increasing  numbers,  with  more  or  less 
fluctuation,  the  maximum  number  being  found  at  the  latter  time, 
after  which  they  begin  to  grow  less  and  less  numerous,  until  by 
about  eight  o'clock  in  the  morning  they  have  practically  all  dis- 
appeared from  the  superficial  circulation  and  reentered  the  deeper 
vessels  in  which  they  remain  until  the  close  of  the  day.  This 
peculiar  periodicity  is  well  illustrated  by  a  recent  series  of  inves- 
tigations made  by  Lothrop  and  Pratt, ^  who  have  charted  the 
phenomenon  in  one  case,  showing  the  approximate  number  of 
parasites  to  the  cubic  millimeter  of  blood  as  follows  :  4  p.  m., 
100;  6  p.  m.,  275  ;  8  p.  m.,  1,300  ;  10  p.  m.,  900  ;  12  m.,  1,500; 
2  a.  m.,  700  ;  4  a.  m.,  900  ;  6  a.  m.,  125  ;  8  a.  m.,  125;  and  10 

^Am.  Journ.  of  Med.  Sc,  1900,  vol.  cxx.,  p.  525. 
2Loc.  cit. 


FILARIASIS.  337 

a.  m.,  loo.  Twenty-one  hundred  embryos  per  cubic  millimeter 
was  the  highest  number  ever  observed  by  these  authors,  the 
specimen  in  which  this  count  was  made  having  been  taken  at 
midnight.  This  characteristic  periodicity,  it  should  also  be  re- 
marked, is  completely  reversed  if  the  individual  harboring  the 
parasite  reverses  his  habits  of  life,  by  sleeping  during  the  day  and 
moving  about  at  night ;  if  such  should  be  the  case  the  worms  will 
appear  in  the  peripheral  blood  during  the  daytime,  the  patient's 
period  of  rest,  and  seek  the  deeper  circulation  at  night,  the  pa- 
tient's period  of  activity. 

The  painstaking  studies  of  Manson,  to  whom  we  owe  most  of 
our  knowledge  of  the  filaria's  life  history,  have  shown  that  the 
mosquito  is  the  intermediate  host  of  this  parasite,  which  may  be 
found  alive  in  the  stomach  of  this  insect  after  it  has  fed  upon  a 
filarious  individual.  Ecdysis  takes  place  in  this  organ,  and  the 
embryos,  after  having  cast  their  sheaths,  manage  eventually  to 
penetrate  the  thoracic  muscles  of  their  host,  in  which  situation 
they  undergo  a  developmental  phase  lasting  for  about  seven  days. 
The  mosquito,  gorged  with  these  partly  mature  parasites,  seeks 
a  stagnant  pool  upon  the  surface  of  which  she  lays  her  eggs,  and 
then  having  died,  falls,  herself,  upon  the  water.  The  filariae  then 
escape  from  the  corpse  of  their  late  host,  and  thus,  through  the 
medium  of  drinking  water,  may  gain  access  to  the  stomach  of 
human  beings.  Having  been  swallowed  by  man,  they  penetrate 
the  stomach  wall  and  Other  tissues,  and  ultimately  reach  some 
part  of  the  lymphatic  system  in  which  they  lodge,  sexually  ma- 
ture, fecundate,  and  beget  the  innumerable  embryos  which  enter 
the  lymph  stream,  and  in  course  of  time  find  their  way  into  the 
circulating  blood. 

Appearance  in  Fresh  Blood:  In  the  unstained  blood-film  the 
parasite  appears  under  the  microscope  as  a  long,  slender,  graceful 
worm  possessing  a  most  remarkable  degree  of  activity.  It  measures 
about  1/80  of  an  inch  in  length,  and  1/3,000  of  an  inch  in  diam- 
eter, and  is  of  a  pearly-gray  color,  with  perhaps  the  faintest  sug- 
gestion of  a  yellowish  tone,  in  certain  lights.  Its  general  appear- 
ance conveys  to  one,  at  first  glance,  the  impression  of  a  thin, 
transparent  tube  through  which  a  rapidly  flowing  stream  of  liquid 
is  constantly  circulating.  The  head  (cephalic  end)  is  gracefully 
rounded,  while  the  tail  (caudal  end)  gradually  tapers  for  about 
one-sixth  the  entire  length  of  the  animal,  and  ends  in  a  fine-pointed 
extremity.  The  worm  is  cylindrical  in  shape,  of  regular  outline, 
and  consists  of  a  central  body  enveloped  in  a  distinct,  loosely 
fitting,  hyaline,  structureless  sheath,  which  is  about  as  much  too 
large  for  the  body  as  the  thumb  of  an  adult's  glove  would  be  for 
22 


338 


GENERAL    HEMATOLOGY. 


the  little  finger  of  a  child.  Thus,  that  part  of  the  sheath  tem- 
porarily unoccupied  by  the  body  is  prone  to  collapse,  folding  upon 
itself  and  trailing  after  the  worm  at  either  or  both  extremities,  as 
a  twisted,  whip-like  ribbon.  The  greater  part  of  the  body  appears 
to  be  of  a  homogeneous  structure  when  examined  in  the  freshly 
prepared  slide,  but  after  the  specimen  has  been  kept  for  several 
hours  coarse  granulations  begin  to  stipple  its  surface,  first  develop- 
ing in  the  center,  and  gradually  spreading  toward  the  periphery. 
(See  Fig.  46.)     A  series  of  fine  striations,  Hke  the  milling  on  a 

Fig.  46. 


FiLAKIA  NOCTURNA. 

Showing  beginning  granular  degeneration  of  the  body  of  the  parasite. 

coin,  may  be  observed  running  along  both  edges  of  the  body,  at 
right  angles  to  its  long  axis.  A  viscus,  appearing  as  a  mass  of 
granular  material,  occupies  a  part  of  the  central  third  of  the  worm's 
body,  running  parallel  to  its  long  axis.  Upon  careful  examination 
with  an  oil-immersion  objective,  rhythmical  dimpling  or  puckering 
movements  may  generally  be  obser\'ed  at  the  tip  of  the  cephalic 
end  of  the  embryo  ;  these  movements,  which  occur  with  more  or 
less  regularity  at  the  rate  of  from  twenty-five  to  forty  times  a 
minute,  have  been  attributed  to  the  act  of  respiration.  As  the 
wriggling  of  the  worm  becomes  less  active,  close  observation  will 
show  that  these  pouting  movements  are  caused  by  the  alternate 
covering  and  uncovering  of  the  cephalic  end  by  a  delicate  six- 


FILARIASIS. 


339 


lipped  prepuce.  The  sudden  projection  and  the  equally  rapid 
retraction  of  a  filamentous  fang  or  tongue-like  organ  from  the 
worm's  uncovered  head  may  also  be  noted  in  some  instances,  but 
this  characteristic  is  so  difficult  to  make  out  that  it  may  usually 
be  looked  for  in  vain.  At  a  point  about  one-fifth  of  the  entire 
length  of  the  worm  posterior  to  the  head  it  is  possible  to  make 
out  a  triangular,  slightly  luminous  patch,  shaped  like  the  letter  V, 
this  spot  being  known  as  the  V-shaped  patch,  regarded  by  Man- 
son  as  a  rudimentary  generative  organ.  A  second  spot,  some- 
what similar  to  it  in  appearance  but  smaller  in  size,  may  occasion- 
ally be  seen  at  a  point  just  above  the  tail  of  the  parasite  ;  this 
spot  Manson  is  incHned  to  regard  as  the  rudimentary  anus. 

The  movements  of  the  worm  are  rapid  and  violent  in  the  ex- 
treme, so  much  so  that  they  are  followed  with  difficulty  with  any 
but  a  low-power  dry  objective.  The  parasite  is  never  at  rest : 
one  moment  it  may  be  curled  up  into  a  tight  bunch,  like  a  coil 
of  rope  ;  the  next  moment  it  may  suddenly  straighten  out  and 
become  rigid  for  an  instant,  only  again  to  resume  its  incessant 
contortions  and  twistings  which  throw  it  into  every  conceivable 
sort  of  shape.  If  particular  attention  is  paid  to  the  point,  it  will 
be  noticed  that,  however  rapid  and  complicated  may  be  its 
movements,  the  parasite  is  never  seen  to  turn  completely  over, 
laterally.  The  accompanying  series  of  sketches,  of  the  filaria 
nocturna  in  a  fresh  blood  slide,  illustrate  a  few  of  the  differ- 
ent forms  which  this  parasite  may  assume.  (Fig.  47.)  The 
worm  seems  to  move  about  among  the  blood  corpuscles  with 
graceful  and  quick  undulations  of  its  body  and  abrupt  whip- 
like strokes  of  its  tail,  butting  its  head  against  the  more  re- 
sisting masses  of  cells  or  else  seeking  a  less  difficult  passage 
around  them,  always  in  motion  but  never,  it  appears,  with  any 
definite  aim  to  its  exertions.  Contrary  to  the  views  expressed 
by  most  observers,  that  the  movements  of  the  filaiia  7ioctiirna 
are  not  truly  propulsive  in  character,  the  writer  has  repeatedly 
noticed  that  this  worm  sometimes  travels  several  times  the  dis- 
tance of  the  diameter  of  the  microscope  field  (one-sixth-inch 
objective,  one-inch  ocular,  and  160  mm.  tube-length),  although 
in  most  cases  its  excursions  were  limited  to  a  measured  area  not 
exceeding  half-a-dozen  square  micromillimeters.  It  cannot  be 
denied  that  these  apparently  progressive  movements  of  the  worm 
may  possibly  be  due  to  the  currents  in  the  blood  plasma,  but  they 
certainly  seem  to  have  every  characteristic  of  a  true  locomotive 
force.  After  the  slide  has  been  kept  for  a  few  hours  the  move- 
ments of  the  worm,  at  first  so  confusingly  rapid,  gradually  become 
slower  and  slower,  and  these  torpid,  more  deliberate  turnings  and 


340 


GENERAL    HEMATOLOGY. 


twistings  may  be  accurately  followed  under  an  immersion  lens. 
If  the  parasite  happens  to  become  confined  in  a  little  pool  of 
plasma  surrounded  by  rouleaux  of  half-dried  erythrocytes,  an 
accident  which  often  happens  when  the  drying  of  the  film  has 


Fig.  47. 


9.<6 


3  48 


9  50 


5.52 


^ 


954 


956 


9.58 


/OOO 


Kl 


/006 


/0  04 


/0.C2 


i 


/OOd 


/o/o 


/0./2 


/0./4  /0/6 


"7^ 


Showing  the  changes   in  the  shape  of  the  filaria  nocturna   during  the  period  of 

HALF  an  hour.  ThE  SKETCHES,  MADE  AT  TWO-MINUTE  INTERVALS,  ALL  REPRESENT  THE  SAME 
PARASITE. 

spread  inward  some  little  distance  from  the  edges  of  the  cover- 
o-lass  its  finer  structure  and  characteristics  may  be  studied  with 
great  ease  and  accuracy. 

The  phenomenon  of  ecdysis,  or  shedding  of  the  worm's  sheath, 
with  the  consequent  escape  of  its  naked  body  into  the  plasma, 
occurs  when  shdes  containing  the  live  filariae  are  kept  for  some 
hours  in  a  cold  (not  freezing)  place.  It  commonly  happens  that 
just  before  the  death  of  the  parasite  an  occasional  erjlhrocyte  or 
leucocyte  becomes  tightly  adherent  to  the  sheath,  swinging  to 
and  fro  with  the  now  lazy,  torpid  movements  of  the  animal. 

Technique  of  Examination.  A  rather  large  drop  of  finger 
blood,  taken  from  the  patient  late  in  the  evening,  preferably 
toward  midnight,  is  placed  between  a  slightly  warmed  slide  and 
cover-glass   the    edges   of   which   are    immediately   sealed   with 


FILARIASIS.  341 

cedar-oil  or  with  vaseline.  The  parasite  should  be  searched  for 
with  a  low-power  dry  objective,  a  two-thirds-inch  lens  being  most 
useful  for  this  purpose,  and  the  attention  of  the  examiner  directed 
especially  to  portions  of  the  field  which  may  show  any  unnatural 
agitation  of  the  blood  cells.  In  specimens  prepared  in  this  man- 
ner the  filariae  will  usually  remain  active  for  several  days,  gener- 
ally for  at  least  forty-eight  hours,  and  sometimes  for  a  longer 
period,  as  in  Henry's  ^  experience,  this  author  having  kept  them 
alive  for  ten  days  in  a  cold  room. 

Staining  the  Filarice.  Films  fixed  for  fifteen  minutes  in  equal 
parts  of  absolute  alcohol  and  ether,  and  stained  with  thionin 
give  the  clearest-cut  pictures,  the  multitude  of  small  nuclei  which 
crowd  the  body  of  the  filariae  being  sharply  differentiated  by  the 
use  of  this  dye.  Fixation  by  heat  or  by  formalin  cannot  be 
employed  without  risk  of  injuring  the  finer  structure  of  the  em- 
bryo. Fair  results  may  also  be  obtained  by  staining  with  methy- 
lene-blue,  or  with  Jenner's  stain,  but  the  definition  is  not  nearly 
so  satisfactory  with  these  dyes  as  it  is  with  thionin.  The  technique 
suggested  by  Manson^  (washing  out  the  hemoglobin  of  the 
erythrocytes  with  water,  drying,  fixing  in  alcohol,  and  staining 
with  methylene-blue  or  with  hematoxylin)  has  usually  proved 
unreliable  in  the  writer's  hands.  The  same  comment  may  be 
made  regarding  attempts  to  demonstrate  the  structure  of  the 
worm  by  staining  with  fuchsin,  as  recommended  by  certain 
authors. 

The  presence  in  the  circulation  of  the  jilaria 

Hemoglobin    noctiirna  does  not  appear  of  itself  to  be  a  factor 

AND  in  the  production  of  any  conspicuous  changes  in 

Erythrocytes,  the  eiythrocytes  and  their  hemoglobin  equivalent, 

if  the  limited  data  at  present  available  may  be 

taken  as  criteria.     The  high-grade  anemia  sometimes  associated 

with    filariasis,  mentioned   by  Ehrlich   and   Lazarus,^  is   due,  no 

doubt,  to  such  complications  as  hematuria,  severe  chyluria,  and 

chronic  diarrhea.     The  following  counts  in  three  cases,  the  first 

two  made  by  the  author,  the  third  by  Lothrop  and  Pratt,"^  may 

be  taken  as  representative  for  the  average  case  : 


Case 


Hemogi 

LOBIN. 

Erythrocytes. 

I. 

Z% 

per 

cent. 

4,876,000,  per  cb. 

mm 

II. 

85 

<( 

4,200,000     "     '' 

<< 

III. 

93 

11 

1  Loc. 

2  Loc. 

3  Loc. 

4  Loc. 

cit. 
cit. 
cit. 
cit. 

6,016,000    ''     *' 

( ( 

342 


GENER.\L    HEMATOLOGY. 


Neither  structural  changes,  nor  irregular  staining  affinities  of 
the  cells,  nor  the  occurrence  of  nucleated  eiythrocytes  have  been 
reported  in  connection  with  the  disease. 

The  number  of  leucocytes  does  not  exceed  the 

Leucocytes,  physiological  limits  of  health,  except  as  the  re- 
sult of  some  complication.  Thus,  in  the  first 
case  quoted  above  the  leucocyte  count  was  found  to  be  41,000 
per  cubic  millimeter,  but  this  increase  was  regarded  purely  as  a 
post-operative  rise,  the  patient  having  been  operated  upon  for  a 
supposed  varicocele  less  than  twenty-four  hours  before  the  blood 
examination  was  made.  The  count  in  the  second  case  was  8,000, 
and  in  the  third  the  counts  were  8,000,  7,400,  and  3,500,  respec- 
tively— an  average  of  6,300. 

The  relative  percentage  of  mononuclear  non-granular  leuco- 
cytes is  somewhat  higher  than  normal,  with  a  consequent  decrease 
in  the  proportion  of  polynuclear  neutrophiles.  The  eosinophiles 
either  remain  at  a  maximum  normal  percentage  or  may  be  dis- 
tinctly in  excess  of  this  figure.  In  Case  II.  the  actual  number  of 
these  cells  to  the  cubic  millimeter  of  blood  was  estimated  at  760, 
the  percentage  being  9.5.  In  this  same  case  it  was  also  observed 
that  the  great  majority  of  lymphocytes  appeared  as  cells  having  a 
deeply  stained  eccentric  nucleus  surrounded  by  an  abnormally 
large  area  of  protoplasm,  the  general  appearance  of  these  cells  be- 
ing similar  to  those  in  the  illustration  shown  on  page  259.  Typical 
coarsely  granular  mast  cells  may  be  found  in  small  numbers  or 
they  may  be  entirely  absent,  as  may  also  be  the  finely  granular 
forms  of  basophiles.  The  presence  of  myelocytes  has  not  been 
noted. 

The  above  qualitative  changes  in  the  leucocytes  may  be  illus- 
trated by  the  following  "first-counts"  of  the  three  cases  men- 
tioned above : 


Forms  of  Leucocytes. 

Case  I. 

Case  II. 

Casein 

Small  lymphocytes. 
Large  lymphocytes. 
Polynuclear  neutrophiles. 
Eosinophiles. 
Mast  cells. 
Myelocytes. 

23. 1  per  cent. 

63.9 

3-4        '' 

0.6 

0.0        " 

34.2  per  cent. 

0.6        - 
55.7        " 

9.5        " 

0.0        *' 

0.0        " 

35-33  per  cent. 
3.67        " 
56.67        " 

4.33        " 
0.0          " 
0.0          " 

The   detection  of  the  filaria  nocturna  in  the 

Diagnosis,     blood   serves  at   once   to  differentiate  idiopatJiic 

from   parasitic    c/iyliiria,   hydrocele    from    lympli 

scrotum,   hernia    and    other  tumors  of  the  groin    from  parasitic 

inguinal  varicosities  (Bancroft's    **  helminthoma    elastica"),   and 


GASTRITIS.  343 

filarial  orchitis  from  other  inflammatory  conditions  of  the  testes. 
Non-parasitic  lymphedema  affecting,  for  example,  the  legs,  can  but 
rarely  be  distinguished  by  the  blood  findings  from  true  elephan- 
tiasis Arabum,  since  in  the  latter  disease  it  is  exceptional  to  find 
filaria  in  the  general  circulation. 

XXI.     FRACTURES. 

Blake,  Hubbard,  and  Cabot'  conclude,  from  a  study  of  38 
cases,  that  in  simple  uncomplicated  fractures  the  number  of  leu- 
cocytes is  seldom  increased  to  any  extent,  a  statement  which  applies 
also  to  complicated  fractures  in  the  great  majoiity  of  instances. 
Of  23  simple  fractures  examined  by  these  authors,  in  but  lO  was 
the  count  higher  than  10,500  per  cubic  millimeter,  and  of  these 
only  6  exceeded  12,000.  The  highest  estimate  was  i  5,400,  in  a 
fracture  of  the  pelvis,  and  the  next  highest,  14,800,  in  a  broken 
leg.  Of  I  5  complicated  fractures,  but  2  showed  any  decided  in- 
crease in  the  number  of  leucocytes,  namely,  a  fracture  of  the  tibia 
and  fibula,  with  symptoms  suggestive  of  fat  embolism,  in  which 
the  count  was  i  5,600  ;  and  a  case  of  fractured  ribs  with  injury  of 
the  lung,  in  which  the  leucocytes  numbered  14,900  two  days 
after  the' accident.  An  estimate  of  5,400  cells  was  made  in  a 
compound  fracture  of  the  leg  two  hours  after  the  accident. 

Lipemia  is  occasionally  met  with  in  fractures  of  the  long  bones 
involving  injury  of  the  fatty  marrow. 

XXII.     GASTRITIS. 

In  the   acute  form  there  is  no  deviation  from 
Hemoglobin    normal  in  the  number  and  hemoglobin  value  of 
AND  the  erythrocytes,  except  in  the  event  of  hyper- 

Erythrocytes.  emesis,  which,  through  concentration  of  the  blood, 
may  cause  a  transient  polycythemia.  In  the 
chronic  form  secondary  anemia  frequently  develops,  and  occasion- 
ally reaches  an  extreme  grade,  should  the  gastric  lesion  be  suffi- 
cient to  interfere  radically  with  the  digestion  and  absorption  of 
food.  In  instances  of  this  sort  the  quantitative  changes  may 
simulate  those  of  true  pernicious  anemia,  but  the  qualitative 
changes  typical  of  this  disease  are  invariably  wanting.  In  pass- 
ing, it  seems  pertinent  to  recall  the  etiological  relationship,  dis- 
tinguished by  some  authorities,  between  gastric  tubule  atrophy 
and  pernicious  anemia.  In  cases  associated  with  gastrectasis 
and  hyperacidity,  blood  inspissation  from  emesis  is  a  common 
change. 

1  Am.  Surg.  Assn.,  Baltimore,  May  7,  1901.      (Personal  communication  from  Dr. 
J.  B.  Blake.) 


344 


GENERAL    HEMATOLOGY. 


A  synopsis  of  J.  A.  Lichty's  studies^  of  the  hemoglobin  and 
erythrocytes  in  98  cases  of  various  gastric  disorders  shows  the 
following  average  values  : 


Condition. 

No.  of  Cases. 

Hemoglobin  Percentage. 

Erythrocytes  per  cb.  mm. 

Hyperchlorhydria. 

39 

90.9 

5,556,000 

Hypochlorhydria. 

13 

83-5 

5,431,000 

Gastric  achvlia. 

6 

92.1 

5,680,000 

Gastric  dilatation. 

II 

85.6 

5,623,000 

Gastric  neurasthenia. 

13 

87.2 

5,274,000 

Chronic  gastritis. 

14 

91.0 

5,498,000 

From  other  investigations,  Lichty  also  determined  that  in  the 
above-named  diseases  there  is  no  definite  relationship  between 
the  condition  of  the  blood,  the  urine,  and  the  gastric  contents. 

In  actite  gastritis  leucocytosis  of  the  poly- 
Leucocytes.  nuclear  neutrophile  type  is  common,  although 
not  constant ;  the  increase  is  most  notable  in  the 
severest  cases,  but  even  in  these  the  count  seldom  exceeds  1 5,000 
or  20,000.  Hyperinosis  also  usually  exists.  .In  chrojiic  cases 
an  absence  of  leucocytosis  is  the  rule,  while  leucopenia,  resulting 
from  defective  absorption,  is  an  occasional  finding.  Relative 
lymphocytosis  is  commonly  associated  with  leucopenia,  and 
sometimes  with  normal  leucocyte  counts.  In  a  small  proportion 
of  cases  digestion  leucocytosis  is  either  delayed  or  absent. 

The  presence  of  a  leucocytosis   is   a  valuable 

Diagnosis,      sign  in  ruling  out  enteric  fever,  should  the  diag- 
nosis lie   between  this  disease  and  acute  febrile 
gastritis.     This  sign,  however,  can  not  be  employed  to  differentiate 
other  acute  infections,  such,  for  instance,  as  appendicitis. 

The  blood  furnishes  no  sure  means  of  dififerentiating  chronic 
gastritis  from  gastric  cancer,  although  a  persistent  leucocytosis  is 
very  suggestive  of  the  latter  ;  unfortunately,  digestion  leucocytosis 
is  neither  constantly  absent  in  cancer  nor  invariably  present  in  gas- 
tritis. 

Certain  cases  of  chronic  gastric  catarrh,  with  atrophy  of  the 
stomach  tubules,  in  course  of  time  develop  a  clinical  picture  veiy 
like  that  of  true  pernicious  anemia,  since  they  present  not  only  a 
similar  cachexia,  but  also  a  very  striking  diminution  in  hemo- 
globin and  erythrocytes.  But  pernicious  anemia  is  characterized 
by  the  presence  of  nucleated  eiythrocytes  the  majority  of  which 
are  megaloblasts,  while  in  the  secondary  anemia  of  gastric  catarrh 
erythroblasts  are  uncommon,  and  if  present  show  a  predominance 
of  cells  of  the  normoblastic  type. 

'  Phila.  Med.  Joum.,  1899,  vol.  iii.,  p.  326. 


GASTRIC    ULCER.  345 

XXIII.     GASTRIC    ULCER. 

The  average  case  shows  a  loss   of  approxi- 
Hemoglobin     mately    40   per    cent,    of    hemoglobin,    and    of 
AND  1,000,000  erythrocytes  to  the  cubic  millimeter, 

Erythrocytes,  and,  owing  to  this  prevalence  of  a  dispropor- 
tionately large  oligochromemia,  low  color  indices 
are  the  rule.  The  individual  case  may  show  a  much  greater 
degree  of  anemia,  but  no  matter  how  marked  the  cellular  decrease, 
it  is  always  far  outstripped  by  the  diminution  in  the  percentage  of 
hemoglobin.  In  fact,  in  some  instances  the  latter  alone  is  subnor- 
mal, the  blood  condition  of  chlorosis  being  thus  faithfully  counter- 
feited.   The  average  index  for  the  cases  tabulated  below  was  0.72. 

Profuse  hemorrhage  may  provoke  a  very  marked  anemia,  while 
protracted  emesis  tends  to  concentrate  the  blood,  thus  masking 
its  real  condition. 

The  several  degenerative  changes  affecting  the  erythrocytes, 
common  to  any  severe  anemia,  may  be  present,  if  the  blood 
deterioration  is  sufficiently  profound.  After  a  severe  hemorrhage 
a  few  normoblasts  not  infrequently  appear  in  the  blood  tempo- 
rarily, and  an  occasional  cell  of  this  type  may  be  found  at  other 
times  in  cases  with  marked  cachexia. 

The  following  summary  illustrates  the  hemoglobin  and  eryth- 
rocyte ranges  in  20  cases  : 

Hemoglobin.  Erythrocytes. 

From  70-80  %  in  5  cases.  Above  5,000,000                    in     i  case. 

**     60-70   '^   '^  6      "  From  4,000,000-5,000,000  ''  10  cases. 

"     50-60   ''   ''  I       '^  "     3,000,000-4,000,000  "  6     '' 

^'     40-50   '*   '^  4      "  *'     2,000,000-3,000,000  '*  3      '' 
''     30-40   ^'   "  2      " 
''     20-30   ''   ''  2      "• 

Average:       57-8%  Average:      4,017,000  per  cb.  mm. 

Maximum:     80.0"  Maximum:    5,200,000    ''     "       " 

Minimum:    25.0''  Minimum:    2,450,000    ''     ''      '' 

Greenough  and  Joslin  ^  report  hemoglobin  estimates  in  73  cases, 
of  which  34  were  below  50  per  cent.,  and  64  below  80  per  cent. 
Of  their  43  erythrocyte  counts,  24  were  below  4,000,000  per 
cubic  millimeter,  the  color  index  for  this  series  averaging  0.67, 
and  ranging  from  0.35  to  1.4 1. 

Absence   of  leucocytosis  is  the  rule,  for  an 
Leucocytes,    increase  occurs  only  after  taking  food,  or  in  the 
event    of  some    complication     such    as    hemor- 
rhage or  perforation.     But  the  fact  must  be  recalled  that  neither  of 

^Am.  Journ.  of  Med.  Sc,  1899,  vol.  cxviii.,  p.  167. 


346  GENERAL    HEMATOLOGY. 

these  two  accidents  invariably  raises  the  count ;  for  example,  hem- 
atemesis  is  a  symptom  in  fully  50  per  cent,  of  patients  suffering 
from  ulcer  of  the  stomach,  yet  in  not  more  than  25  per  cent,  of 
all  cases,  both  those  with  and  those  without  this  symptom,  does 
the  number  of  leucocytes  exceed  10,000  to  the  cubic  millimeter. 
The  behavior  of  the  leucocytes  in  the  above-mentioned  series 
of  cases  may  be  expressed  thus  : 


Above 

10,000                in  5 

cases 

From 

8,000-10,000   '^  3 

(( 

(I 

6,000-  8,000   "  5 

(( 

11 

4,000—  6,000   "  6 

(( 

Cl 

2,000-  4,000   "   I 

case. 

Average  :         8, 188  per  cb. 

mm. 

Maxinium  :    16,000     "     '' 

a 

Minimum  :      2,400     '^    '' 

i  I 

In  cases  with  leucocytosis  the  increase  affects  chiefly  the  poly- 
nuclear  neutrophiles  ;  in  those  without  leucocytosis  minimum  nor- 
mal or  distinctly  subnormal  percentages  of  these  cells  are  not  un- 
common, and  a  total  absence  of  eosinophiles  is  the  general  rule, 
these  changes  being  counterbalanced  by  a  proportionate  increase 
in  the  small  lymphocytes. 

Hematology  gives  no  aid  in  distinguishing  gas- 
DiAGNOSiS.      trie    ulcer  from    gastralgia,   duodenal  ulcer  and 
simple  gall-stone  colic,  in  all  of  which  leucocytosis 
is  absent.      The  differences  in  the  blood-pictures  of  gastric  ulcer 
and  cancer  are  referred  to  under  the  latter  disease.     (See  "Malig- 
nant Disease.") 

XXIV.     GLANDERS. 

Data  are  wanting  regarding  the  condition  of  the  hemoglobin  and 
erythrocytes  in  human  glanders,  but  it  is  known  that  leucocytosis  is 
the  rule.  The  bacillus  mallei  has  been  obtained  by  ante-mortem 
blood  culturing,  by  Duval.^ 

XXV.     GONORRHEA. 

The  hemoglobin  and  erytJirocytes  are  unaltered,  but  the  acute 
febrile  stage  of  specific  urethritis  is  usually  accompanied  by  a 
moderate  polynuclear  leucocytosis,  which,  in  the  event  of  any  of 
the  inflammatory  complications  of  clap,  may  be  much  aggravated. 
Some  authors  formerly  claimed  that  circulatory  eosinophilia  was 
a  feature  of  this  disease,  but  the  more  recent  investigations  of 
Vorbach  -  have  shown  that  such  a  change,  while  occurring  some- 

1  Archiv.  de  med.  exper. ,  1896,  vol.  viii.,  p.  361. 
2Inaug.  Dissert.,  Wurzburg,  1 895. 


GOUT.  347 

times,  is  by  no  means  constant ;  he  found  in  twenty  cases  that 
the  percentage  of  eosinophiles  ranged  from  as  low  as  0.05  to  as 
high  as  1 1.5.  Bettman^  believes  that  eosinophilia  is  especially 
frequent  in  posterior  urethritis,  an  observation  which  thus  far  is 
unique. 

XXVI.     GOUT. 

Garrod's^  earlier  teachings  regarding  the  lowered  alkalinity  of 
the  blood  in  acute  gout  have  been  contradicted,  apparently  with 
ample  proof,  by  the  later  researches  of  Levy,^  who  failed  to  find 
a  diminution  in  any  of  the  17  cases  which  he  investigated  by 
the  most  approved  methods.  Still  more  recently,  Levy's  con- 
clusions have  been  corroborated  by  the  studies  undertaken  by 
Watson.^  During  an  acute  gouty  seizure  hypeririosis  is  an  al- 
most invariable  finding. 

It  is  questionable  whether  or  not  the  amount  of  uric  acid  in  the 
blood  is  greater  during  the  acute  stages  than  in  the  interval  be- 
tween them,  but  it  is  nevertheless  a  fact  that  in  many  gouty 
persons  uric  acid  crystals  may  be  demonstrated  in  the  blood  by 
the  '*  thread-test" — a  reaction  by  no  means  peculiar  to  this 
disease,  as  already  pointed  out.     (See  page  109.) 

The  cellular  elements  show  no  characteristic  alterations,  and 
are  normal  except  in  long-standing  cases  in  which  an  ordinary 
secondary  anemia  may  develop  in  the  course  of  time.  During 
the  acute  attack  a  moderate  increase  in  the  number  of  leucocytes, 
affecting  chiefly  the  polynuclear  neutrophiles,  may  or  may  not  be 
found.  A  relative  increase  in  the  eosinophiles  is  also  sometimes 
encountered,  both  in  cases  with  and  without  an  increase  in  the 
leucocyte  count.  In  one  case  of  the  writer's,  the  blood  examined 
during  the  height  of  a  severe  paroxysm  showed  100  per  cent,  of 
hemoglobin,  7,125,000  erythrocytes,  and  14,000  leucocytes  per 
cubic  millimeter,  the  only  peculiar  differential  change  being  the 
presence  of  myelocytes  in  the  proportion  of  0.4  per  cent.  The 
occurrence  of  these  cells  in  gout  has  also  been  mentioned  by  Wat- 
son,^ who  found  them  in  small  numbers  both  during  and  between 
the  acute  seizures.     (See  page  107.) 

The  same  observer  also  states  that  he  found  (apparently  in  in- 
creased numbers),  cells  resembling  blood  plaques,  as  large  as  4^ 
in  diameter,  often  forming  '*  very  irregular  torn-looking  masses." 

1  Archiv.  f.  Dermat.  u.  Syph.,  1899,  vol.  xxxix.,  p.  227. 
2"  Gout  and  Rheumatic  Gout,"  London,  1876,  p.  80. 
3Zeitschr.  f.  klin.  Med.,  1898,  vol.  xxxvi.,  p.  336. 
*  British  Med.  Journ.,  1900,  vol.  i.,  p.  lO. 
^Loc.  cit. 


348  GENERAL    HEMATOLOGY. 

The  worthlessness  of  Neusser's  so-called  perinuclear  basophilic 
granules  as  a  diagnostic  sign  of  this  condition  has  been  alluded 
to  in  a  previous  section.      (Page  1/6.) 

XXVII.     HEMORRHAGIC    DISEASES. 

From  a  hematological  standpoint,  scurvv,  heui- 
Gexeral       ophilia,   and  the  various  forms   of  purpura  may 

Features,      be  conveniently  considered   together,  since    the 
blood  changes  in  all  of  these  conditions  are  sim- 
ilar, and  in  none  are  characteristic. 

The  specific  gravity  of  the  blood  varies  with  the  degree  of 
anemia  present,  but  only  in  exceptional  instances  does  it  fall  to 
an  excessively  low  figure.  Aiello  ^  estimated  it  as  low  as  1043, 
in  a  case  of  purpura  hemorrhagica  in  which  the  erythrocyte  loss 
ranged  between  50  and  60  per  cent.  The  same  investigator  also 
detected  methemoglobin  in  the  blood,  by  spectroscopical  examina- 
tion, in  this  form  of  purpura,  which  he  attnbutes  directly  to  auto- 
intoxication from  the  absorption  of  the  products  of  decomposition 
occurring  within  the  intestinal  canal.  Immerman "  believed  that 
in  the  late  stages  of  hemophilia  an  increase  in  the  total  quantity 
of  the  blood,  or  a  true  plethora,  exists,  but  this  view  is  not  enter- 
tained at  the  present  time. 

Various  bacteria,  especially  streptococci,  staphylococci,  and 
bacilli,  have  been  found  in  the  circulating  blood  by  a  number  of 
observers,  both  in  scurvy  and  in  those  forms  of  purpura  due  to 
infectious  diseases.  No  special  clinical  significance,  however,  can 
be  attached  to  these  findings.  The  specific  properties  claimed  by 
Letzerich  ^  for  his  bacillus  purpurcB  are  not  generally  credited. 

The  alkalinity  of  the  blood,  according  to  the  studies  of  Cantani^ 
and  others,  is  generally  decreased  in  the  hemorrhagic  diatheses, 
although  more  recent  investigators  have  disputed  this  fact,  having 
found  it  higher  than  normal.  Wright^  has  recently  estimated 
the  alkalinity  in  7  cases  of  scurvy,  a  disease  which  he  believes  to 
be  a  condition  of  acid  intoxication.  He  found  in  3  of  these  cases 
that  it  corresponded  to  the  figure  N.  100,  and  to  N.  200,  N.  150, 
N.  1 10,  and  N.  80,  respectiv^ely,  in  the  remaining  4.  As  de- 
termined bv  this  author's  method,  the  alkalinitv  of  normal  blood 
is  expressed  by  the  formula  N.  35,  which  means,  in  other  words, 
that  the  degree  of  alkalinity  is  such  that  a  mixture  of  one  volume 

^  Rif.  med.,  1894,  vol.  ii.,  p.  103. 

^Ziemssen's  Handb.  spez.  Pathol,  u.  Ther.,  1879,  vol.  xiii.,  p.  2. 

^Zeitschr.  f.  klin.  Med.,  1890,  vol    xviii.,  p.  517. 

*  "  Spez.  Pathol,  u.  Ther.  der  Stoffwechselkrankh.,''  Leipzig,  1884. 

^Lancet,  1900,  vol.  ii.,  p.  1556. 


HEMORRHAGIC    DISEASES. 


349 


of  a  thirty-five-fold  diluted  normal  acid  with  an  equal  volume  of 
blood  serum  is  just  sufficient  to  prevent  the  latter  from  reacting 
with  sensitive  blue  litmus  paper. 

The  coagulation  of  the  fresh  blood  drop  is,  as  a  rule,  slow,  and 
sometimes  incomplete,  these  characteristics  being  observed  with 
especial  frequency  in  hemophilics.  In  such  subjects  Wright ' 
determined  that  clotting  may  fail  to  occur  until  after  the  lapse  of 
over  an  hour  after  the  withdrawal  of  the  blood  from  the  vessels, 
while  in  other  instances  the  coagulation  time  ranged  from  9  to  14 
minutes.  Grawitz  ^  has  called  attention  to  the  fact  that  in  cases 
with  long-continued  hemorrhage  the  clotting  may  be  abnormally 
rapid,  as  is  the  case  with  normal  blood  after  this  accident. 

There  are  no  characteristic  changes  affecting 
Hemoglobin     the    erythrocytes    and    hemoglobin,  the    blood- 
AND  picture  being  that  of  secondary  anemia  of  variable 

Erythrocytes,  intensity.  In  the  majority  of  well-marked  cases 
the  erythrocytes  do  not  suffer  a  loss  of  more  than 
1,000,000  or  2,000,000  to  the  cubic  milHmeter,  but  the  hemo- 
globin tends  toward  a  proportionately  greater  decrease,  making  a 
low  color  index  the  rule.  This  is  particularly  noticeable  in  scurvy 
in  which  condition  the  hemoglobin  loss  is  often  twice  as  great 
as  that  of  the  cells  ;  in  fact,  some  cases  show  simply  oligochro- 
memia,  with  a  normal  number  of  erythrocytes.  In  7  cases  of 
infantile  scurvy,  examined  by  the  writer,  the  hemoglobin  percent- 
age ranged  between  35  and  65,  averaging  43.8,  and  the  erythro- 
cyte count  between  2,950,000  and  5, 100,000  per  cubic  millimeter, 
the  average  being  3,527,071.  In  three  of  these  cases,  with 
counts  of  5,100,000,  4,900,000,  and  4,814,000,  respectively,  the 
corresponding  hemoglobin  estimates  were  52,  50,  and  65  per 
cent.  In  severe  cases,  for  example,  of  scurvy  and  purpura 
hemorrhagica,  the  count  may  fall  to  less  than  1,000,000  and  the 
hemoglobin  to  20  per  cent,  or  lower,  these  changes  being  accom- 
panied by  all  the  qualitative  alterations  typical  of  a  profound 
secondary  anemia  which  sooner  or  later  may  prove  fatal.  Muir^ 
reports  a  case  of  purpura  in  which  the  hemoglobin  was  only  1 1 
per  cent.,  and  the  erythrocytes  800,000  per  cubic  millimeter,  and 
still  more  pronounced  losses  have  been  occasionally  encountered 
by  other  observers.  In  mild  cases  the  blood  may  be  absolutely 
normal  in  every  respect.  Regeneration  is  rapid  in  cases  which 
pursue  a  favorable  course.  It  is  well  known  that  hemophilics 
appear  to  be  less  susceptible  to  the  ill  effects  of  hemorrhage  than 

J  British  Med.  Journ.,  1893,  vol.  i.,  p.  223. 

2  Loc.  cit. 

'^ British  Med.  Journ.,  1900,  vol.  ii.,  p.  909. 


350  GENERAL    HEMATOLOGY. 

other  individuals,  and  that  in  this  condition  recovery  from  bfood' 
losses  is  usually  rapid  and  uneventful,  in  spite  of  their  number, 
extent,  and  chronicity. 

The  leucocytes  are  usually  increased  both  in 
Leucocytes,  purpura  and  in  scurvy,  but  in  hemophilia  a  de- 
cided leucopenia  may  develop  in  spite  of  the  ex- 
isting hemorrhages.  The  increase  is  typically  polynuclear  in 
most  instances,  although  a  relative  excess  of  lymphocytes  may 
occur.  Stengel  ^  found  this  change  most  striking  in  two  cases  of 
purpura  hemorrhagica,  and  the  writer  has  noticed  an  exaggeration 
of  the  lymphocytic  tendency  of  children's  blood  in  a  number  of 
cases  of  infantile  scurvy.  In  4  of  the  7  cases  of  this  condition, 
referred  to  in  the  preceding  paragraph,  the  total  percentage  of 
lymphocytes  was  between  60  and  66  ;  in  3  the  percentage  of 
polynuclear  neutrophileswas  from  27  to  35  ;  the  eosinophiles  aver- 
aged a  low  normal  figure,  and  in  all  but  a  single  case  myelocytes 
were  found,  ranging  in  percentage  from  a  minimum  of  i  to  a 
maximum  of  6,  and  averaging  2.5  per  cent.  The  actual  number 
of  leucocytes  varied  between  8,000  and  25,000,  and  averaged 
1 5,5 57  per  cubic  millimeter,  all  but  a  single  case  having  a  decided 
increase.  Denys^  has  called  attention  to  the  presence  of  large 
numbers  of  leucocytes  in  the  different  stages  of  degeneration, 
both  in  scurvy  and  in  the  infectious  form  of  purpura. 

In  all  the  hemorrhagic  conditions  above  men- 

Blood         tioned,  the  blood  plaques  are  usually  much  di- 

Plaques.       minished    in    number,    and    sometimes    absent. 

Especially   is   this   the   case   in   grave    forms   of 

scurvy  and  of  purpura  hemorrhagica.      Hayem  ^  believes  that  a 

marked  diminution  in  the  number  of  plaques  plus  a  deficiency  in 

clotting  is  a  pathognomonic  sign  of  the  latter  disease. 

'-  XXVIII.    HEPATIC  CIRRHOSIS. 

In  the  early  stages  of  atropine  cirrhosis,  so  long 

Hemoglobin     as  the  patient's  general  health  is  maintained,  the 

and  blood  remains  practically  normal,  or  shows,  per- 

Erythrocytes.  haps,  only  a  moderate  diminution  in  hemoglobin. 

But  as  the  disease    progresses,  and  the  patient 

suffers  from  gastro-intestinal  catarrh,  hemorrhages,  and  circulator}^ 

embarrassment,   an  ordinary  secondary  anemia  sooner    or  later 

becomes  apparent,  the  intensity  of  this  change  depending  upon 

the  severity  of  the  primary  disease    and  its  associated  lesions. 

1  "Twentieth  Centur}'  Practice  of  Medicine,"  N.  Y.,  1896,  vol.  vii.,  p.  485. 
2Centralbl.  f.  allg.  Pathol.,  1893,  vol.  iv.,  p.  174. 
^Compt.  rend.  I'Acad.  sc,  Paris,  1896,  vol.  cxxiii.,  p.  894. 


HEPATIC    CIRRHOSIS.  35  I 

Most  advanced  cases  show  a  loss  of  from  2,000,000  to  3,000,000 
cells  to  the  cubic  millimeter,  and  a  few  an  even  greater  oligo- 
cythemia. Hemorrhages,  either  repeated  and  small,  or  single 
and  profuse,  constitute  the  factor  of  a  profound  anemia  in  many 
instances.  The  average  case  of  Laennec's  cirrhosis  loses  more 
than  50  per  cent,  of  hemoglobin  and  30  per  cent,  of  erythrocytes, 
while  in  the  individual  case  the  count  may  fall  to  between  1,500,- 
000  and  2,000,000.  The  color  index,  as  a  rule,  is  moderately 
low  ;  it  averaged  0.70  for  a  series  of  18  well-advanced  cases  ex- 
amined at  the  German  Hospital,  a  synopsis  of  which  shows  these 
hemoglobin  and  erythrocyte  values  : 

Hemoglobin         Number  of  Erythrocytes  Number  of 

Percentage.  Cases.  per  cb.  mm.  Cases. 

From  70  to  80  2  From  4,000,000  to  5,000,000  4 

''      60  to  70  2  *'      3,000,000  to  4,000,000  7 

**      50  to  60  5  "      2,000,000  to  3,000,000  6 

*'      40  to  50  6  **      1,000,000  to  2,000,000  1 


It 


30  to  40 


Average:       47.8  per  cent.     Average:      3,404,000  per  cb.  mm. 
Maximum:   80.0    "       '^        Maximum:   4,850,000    ''     "       '' 
Minimum:    37.0    "       **        Minimum:    1,800,000    **     *'      '' 

The  effects  upon  the  blood  of  ascites  are  probably  twofold  and 
diametrically  opposed.  Primarily  it  is  thought  to  cause  more  or 
less  anemia  by  reason  of  the  steady  drain  exerted  upon  the 
albuminoids  of  the  blood,  but  this  deterioration  may  be  effectually 
masked  by  a  polycythemia  due  either  to  peripheral  stasis,  or  to 
inspissation  of  the  blood  caused  by  the  rapid  transudation  of  liquids 
from  the  vessels.  This  last  factor  is  no  doubt  the  cause  of  the 
polycythemia  noted  by  von  Limbeck  ^  in  cases  after  tapping.  On 
the  other  hand,  Grawitz  ^  has  demonstrated  that  a  decrease  in  the 
hemoglobin  and  erythrocyte  values  may  follow  this  operation,  in 
cases  in  which  the  presence  of  a  large  ascitic  exudate  interferes 
with  the  circulation  sufficiently  to  produce  capillary  stagnation  and 
a  consequent  polycythemia,  which  the  tapping  dispels. 

Anemia  is  apparently  more  striking  and  more  common  in 
hypertropJiic  cirrhosis  than  in  ordinary  gin-liver.  Judging  from 
a  rather  limited  experience  in  6  cases,  the  writer  finds  a  greater 
tendency  toward  corpuscular  than  hemoglobin  loss,  and  conse- 
quently toward  higher  color  indices.  The  index  for  these  cases 
averaged  0.88,  and  in  two  it  reached  the  figures  1.02  and  i.oo, 
respectively.     For  the  series  the  hemoglobin  averaged  51.5  per 

1  Loc.  cit. 

2  Log.  cit. 


352  GENERAL    HEMATOLOGY. 

cent.,  the  minimum  being  22,  and  the  maximum  80  per  cent. 
The  average  erj^throcyte  count  was  2,908,333,  and  ranged  from 
as  low  as  1,100,000  to  as  high  as  4,290,000  per  cubic  millimeter. 

The  usual  degenerative  and  other  qualitative  changes  accom- 
panying any  sev^ere  secondar>^  anemia  may  be  found  in  the  anemias 
of  liver  cirrhoses ;  and,  in  addition,  Hayem  ^  has  obser\'ed  that  in 
the  hypertrophic  variety  there  seems  to  be  a  marked  tendency 
toward  megalocytosis. 

In  the  great  majority  of  atrophic  cirrhoses  the 

Leucocytes,  number  of  leucocytes  either  remains  normal  or  is 
distinctly  decreased,  while  a  few  show  a  moderate 
degree  of  intermittent  leucocytosis,  to  be  regarded  in  all  proba- 
bility, as  a  post-hemorrhagic  change.  It  is  questionable  whether 
or  not  the  jaundice  present  in  some  cases  accounts  for  a  leucocyte 
increase,  although  some  authorities  profess  this  belief.  The  leu- 
cocytes in  the  18  cases  tabulated  above  ranged  thus  : 

Leucocytes  per  cb.  mm. 

From  10,000—15,000  in    4  cases. 

"       5,000—10,000  "    9      *' 
Below  5,000  ^'    5     '^ 

Average:         7? 708  per  cb.  mm. 
Maximum:    12,000     **    "       " 
Minimum:      3,000     ''     "      *' 

In  the  6  cases  of  hypertropliic  cirrhosis  the  leucocytes  averaged 
8,800  per  cubic  miUimeter,  the  lowest  count  being  4,400,  and  the 
highest  14,800.  Two  of  the  estimates  were  above,  and  4  below, 
10,000  cells  to  the  cubic  millimeter.  Much  higher  counts  than 
these,  however,  have  been  reported  by  others.  While  it  must  be 
admitted  that  leucocytosis  is  more  frequent  in  this  than  in  the 
atrophic  variety,  Hanot  and  Meunier's  ^  claim  that  it  is  a  constant 
symptom  of  hypertrophic  cirrhosis  is  by  no  means  justified. 

The  leucocytoses  of  both  these  forms  of  the  disease  depend 
upon  an  absolute  and  relative  increase  in  the  polynuclear  neutro- 
philes,  at  the  expense  of  the  other  forms  of  cells. 

The  blood  examination  fails  to   provide  any 

DLA.GNOSIS.      dependable    signs  by  which   cirrhosis  is   distin- 
guishable from   other   lesions   of   the   liver,   but 
a  good  idea  of  the  inroads  made  by  the  disease  upon  the  pa- 
tient's health  may  be  gained  by  determining  from  time  to  time 
the  grade  of  the  anemia  present. 

1  "  Du  Sang,"  etc.,  Paris,  1 889. 

2Compt.  rend.  Soc.  biol.,  Paris,  1895,   IDS.,  vol.  ii.,  p.  49. 


ICTERUS. 


353 


XXIX.    HERPES    ZOSTER. 

The  blood  changes  in  shingles  have  recently  been  studied  by 
Samrazes  and  Mathias/  who  found  no  appreciable  diminution  in 
the  hemoglobin  and  erythrocytes,  and  no  structural  changes  affect- 
ing the  latter.  Leiicocytosis  develops  as  early  as  the  first  day  of 
the  eruption,  and  progressively  increases  until  about  the  third  day, 
after  which  it  gradually  diminishes,  until  by  the  fifth  day  the 
count  again  reaches  the  normal  figure.  A  secondary  leucocytosis 
accompanies  the  period  of  desiccation  and  desquamation.  A  gain 
in  the  polynuclear  neutrophiles  and  eosinophils  is  accountable 
for  the  leucocytosis,  which  in  some  instances  is  associated  with 
a  few  myelocytes. 

XXX.    ICTERUS. 

Simple  catarrhal  jaundice,  perse,  produces  little 
General       or  no  effect  upon  the  blood,  except  in  the  most 
Features,      pronounced  cases.    The  most  conspicuous  change 
consists  in  a  greenish-yellow  discoloration  of  the 
serum,  due  to  the  presence  of  bile.     In  patients  suffering  from 
obstructive  jaundice  (due,  for  instance,  to  gall-stones),  a  surgical 
operation  may  be  complicated  by  dangerous,  even  fatal  hemor- 
rhage, owing  to  the  slow  and  imperfect  coagulation  of  the  blood. 
In  the  Jefferson  Hospital,  during  the  past  three  years,  four  pa- 
tients with  jaundice  due  to  malignant  disease  of  the  biliary  appa- 
ratus have  bled  to  death  after  operation.      The  quantity  oi fibrin  is 
not  increased.     The  specific  gravity  of  the  whole  blood  increases 
in  relation  to  the  intensity  of  the  icterus,  but  the  density  of  the 
serum  is  unaffected.     In  severe  cases  the  alkalinity  of  the  blood 
was  found  to  be  reduced,  by  de  Rienzi.^ 

In  mild  cases  the  hemoglobin  and  erythrocytes 
Hemoglobin    remain  unaltered,  but  in  severe  jaundice  a  mod- 
AND  erate  anemia  is  not  uncommon,  characterized  by 

Erythrocytes,  an  absence  of  rouleaux  formation,  and  by  evi- 
dences of  endoglobular  degeneration  marked  out 
of  all  proportion  to  the  grade  of  the  cellular  decrease.  This 
association  of  a  moderate  oligocythemia  with  striking  degenera- 
tive changes  in  the  corpuscles  appears  to  be  peculiar  to  this  affec- 
tion. In  cases  with  symptoms  of  cholemia  these  degenerative 
changes  are  even  more  notable,  but  here  the  hemoglobin  and 
erythrocyte  losses  also  are  more  pronounced.  Von  Limbeck^ 
has   observed  that  the  volume  of  the  individual  erythrocyte  is 

^  Rev,  de  sc.  med.,  1901,  vol.  xxi.,  p.  251. 
^Virchow's  Archiv.,  1885,  vol.  cii. ,  p.  218. 
3  i^c,  cit. 

23 


354  GENERAL    HEMATOLOGY.- 

markedly  increased.  It  is  possible  that  in  some  instances  the 
anemia  is  actually  greater  than  the  blood  count  indicates,  for 
polycythemia,  according  to  Becquerel  and  Rodier,^  may  develop 
by  reason  of  inspissation  of  the  blood  from  the  action  of  bile. 

Most  observers  report  that  no  leucocytosis 
Leucocytes,  occurs  in  simple  catarrhal  jaundice,  but  Grawitz,^ 
on  the  contrary,  states  that  he  finds  a  constant 
increase  in  "uncomplicated  cases  of  icterus,"  the  count  ranging 
in  some  instances  as  high  as  from  30,000  to  40,000  to  the  cubic 
millimeter.  This  author's  report,  however,  does  not  represent 
the  general  consensus  of  opinion.  Severe  cases  with  cholemia 
may  and  usually  do  give  rise  to  a  well-developed  leucocytosis. 

The   association  of  icterus  with  leucocytosis. 

Diagnosis,     except  in  obviously  cholemic  patients,  suggests 

some  purulent  lesion,  or  malignant  disease  as  the 

factor  of  jaundice,  rather  than  uncomplicated  duodeno-cholangitis. 

XXXI.     INFLUENZA. 

General  invasion  of  the  circulation  by  the  bacillus  infliienzce 
occurs  very  rarely,  and  the  positive  results  from  bacteriological 
exainination  of  the  blood  claimed  by  Canon,^  Klein,^  and  their 
contemporaries  must  be  regarded  as  unsubstantiated,  in  the  light  of 
the  large  number  of  negative  findings  by  Pfeiffer,^  and  by  Kiihnau.^ 
Slawyk  ^  has  recently  succeeded  in  cultivating  this  organism  from 
the  blood  of  a  patient  whose  predominant  symptoms  suggested 
epidemic  meningitis.  Jehle,^  although  he  admits  the  rare  occur- 
rence of  Pfeiffer's  bacillus  in  the  blood  of  uncomplicated  influenza, 
claims  to  have  obtained  many  positive  blood  cultures  of  this 
organism  in  diphtheria,  in  pertussis,  and  in  several  of  the  ex- 
anthemata— measles,  scarlet  fever,  and  varicella.  He  attributes 
these  findings  to  the  fact  that  these  diseases  predispose  to  a 
secondary  infection,  especially  to  an  influenzal  bacteriemia. 

The  Jieinoglobin  and  erythrocytes  are  normal  in  the  great  ma- 
jority of  cases,  a  moderate  diminution  in  these  elements  having 
been  found  only  occasionally. 

Uncomplicated  influenza  is  one  of  the  few  examples  of  an  acute 
infection   unaccompanied  by  a  leucocytosis^  although   in  some  in- 

lArchiv.  de  Physiol,  norm,  et  path.,  1874,  2  s.,  vol.  i.,  p.  509. 

2Loc.  cit. 

^Virchow's  Archiv.,  1893,  vol.  cxxxi.,  p.  401. 

*  Baumgarten' s  Jahresb. ,  1893,  vol.  ix.,  p.  206. 

SDeut.  med.  Woch.,  1893,  vol.  xix.,  p.  816. 

^Loc.  cit. 

''Zeitschr.  f.  Hyg.  u.  Infectionskr. ,  1899,  vol.  xxxii.,  p.  443. 

^Zeitschr.  f.  Heilk.,  1901,  vol.  xxii.,  p.  190. 


INSOLATION.  35  5 

stances  Jiyperiiiosis  may  be  observed  in  the  early  stages  of  the 
attack.  Rieder  ^  states  that  a  complicating  catarrhal  pneumonia 
causes  either  a  moderate  increase  in  the  number  of  leucocytes,  or 
none  at  all,  but  that  in  a  post-influenzal  croupous  pneumonia  the 
leucocytosis  of  this  condition  develops  typically. 

It  is  unfortunate  that  an  absence  of  leucocytosis  is  common  to 
both  enteric  fever  and  influenza,  for  these  two  diseases  are  not  in- 
frequently confused.  The  serum  test,  however,  generally  is  con- 
clusive, if  typhoid  exists.  Should  a  frank  leucocytosis  be  pres- 
ent, croupous  pneumonia,  rather  than  influenza,  is  suggested. 

XXXII.    INSOLATION. 

In  the  acute  stages  of  thermic  fever  the  Jiemoglobin  and  ery- 
tJirocyte  values  are  unduly  high,  owing  to  the  concentration  of 
the  blood  from  the  excessive  loss  of  body  fluids  by  the  lungs  and 
the  skin.  Lambert,^  for  example,  has  observed  a  hemoglobin 
percentage  of  125  in  a  sunstroke  patient,  while  Vincent^  states 
that  the  erythrocytes  may  number  as  high  as  300,000  per  cubic 
.millimeter  in  excess  of  the  normal  average  count.  A  more  or  less 
pronounced  destruction  of  the  erythrocytes  also  occurs  both  dur- 
ing and  after  the  acute  stages  of  insolation,  and  this  factor  is  re- 
sponsible for  the  anemia,  sometimes  decided,  which  subsequently 
develops.  Owing  to  the  coexistence  of  these  two  conflicting  fac- 
tors, the  real  extent  of  the  hematolysis  cannot  be  determined  until 
after  the  disappearance  of  the  symptoms  leading  to  blood  concen- 
tration. This  hematolysis  is  thought  to  depend  upon  the  presence 
in  the  blood  of  some  toxic  element,  since  the  hyperpyrexia  itself 
is  insufficient  to  cause  disorganization  of  the  cells.  Schultze  and 
Ranvier's  experiments  *  have  proved  that  such  changes  begin  only 
when  an  animal  is  subjected  to  a  temperature  of  from  54°  to  56° 
C.  (or  129.2°  to  132.8°  F.).  Levene  and  Van  Gieson^  have 
shown  that  the  blood  serum  of  sunstroke  patients  is  a  highly  ac- 
tive blood-poison  to  animals,  when  injected  intravenously. 

Some  investigators  have  found  an  increased  number  of  leuco- 
cytes, but  others  have  been  unable  to  detect  any  such  change,  so 
that  leucocytosis  must  be  regarded  as  an  inconstant  sign,  depend- 
ing, perhaps,  more  upon  the  degree  of  blood  condensation  than 
upon  any  specific  influence  of  the  heat-stroke.  Pigmented  leuco- 
cytes have  been  observed  in  cases  in  which  there  existed  marked 
signs  of  blood  destruction. 

1  Miinch.  med.  Woch.,  1892,  vol,  xxxix,,  p.  51 1. 

2  Loomis-Thompson  :  "A  System  of  Practical  Medicine,"  N.  Y.,  1898,  vol.  iii., 
p.  877. 

3  These  d.  Bordeaux,  1887-88,  n.  8,  p.  7. 
*  Cited  by  Vincent :  loc.  cit. 

5  Cited  by  Lambert :  loc.  cit. 


356  GENERAL    HEMATOLOGY. 

Wood  ^  found  that  a  decreased  alkalinity  or  even  an  acidity  of 
the  blood  was  a  conspicuous  post-mortem  change,  but  evidence 
is  lacking  to  show  that  the  reaction  of  the  blood  is  altered  during 
life. 

XXXIII.     INTESTINAL    HELMINTHIASIS. 

The  presence  in  the  intestinal  canal  of  certain 
General  parasites,  notably  the  bothriocephalus  latus  and 
Features,  the  ankylostomum  duodenale,  is  capable  of  pro- 
voking; anemia  of  marked  intensitv  in  the  indi- 
vidual  harboring  them.  The  ascaris  lumbricoides  also  may  be 
held  responsible  for  anemia  in  some  instances,  but  the  blood 
changes  attributable  to  this  parasite  are  as  a  rule  much  less  pro- 
found than  those  commonly  met  with  in  the  two  preceding  forms 
of  helminthiasis.  Ostrovosky  -  has  called  attention  to  a  case, 
uhique  of  its  kind,  of  fatal  progressive  anemia  attributable  to  the 
presence  in  the  intestines  of  the  long  threadworm,  trichocephalus 
dispar.  The  cause  of  these  anemias  is  generally  attributed  to  the 
systemic  effects  on  the  host  of  certain  soluble  and  absorbable 
toxic  products  eliminated  by  the  parasites.  That  such  poisons 
are  produced,  and  that  they  undoubtedly  can  act  in  this  dele- 
terious manner  has  been  abundantly  proved  by  many  different 
investigators,  among  whom  Hubner,^  Reyner,'^  Schaumann,^  As- 
kanazy,^  and  Lussana"  may  be  named  as  authorities  whom  the 
student  should  consult  for  more  detailed  information  on  this  topic. 
It  is  probable  also  that  in  cases  of  ankylostomiasis  the  anemia  is 
kept  up  by  the  constant  drain  on  the  system  caused  by  the  direct 
abstraction  of  blood  by  the  parasite. 

The    blood    changes    due  to   bothriocephalus 

Hemoglobin    latus    infection  are  by  far  the   most  interesting, 

AND  from  the  clinician's  standpoint,  since  the  anemia 

Erythrocytes,  caused  by  this  worm  may  in   some  individuals 

exactly  simulate  primary  pernicious  anemia.    The 

blood-pictures  of  the  two  conditions  may  be  identical,  both  being 

characterized  by  marked  and  disproportionate  oligocythemia,  and 

consequently   by   a  high   color  index,  and   by   the   presence  of 

nucleated  er^'throcytes,  the  majority  of  which  conform  to    the 

megaloblastic  type.     This  so-called  bothriocephalus  anemia  has 

1  "  Thermic  Fever  or  Sun-stroke"  (Boylston  Prize  Essay),  Phila.,  1872. 

2Vratch,  Sept.  30,  1900.     Abstr.,  N.  Y.  Med.  Journ.,  1900,  vol.  Ixxii.,  p.  826." 

'Deutsch.  Archiv.  f.  klin.  Med.,  1870,  vol.  vii.,  p.  7. 

*  Ibid.,  1886,  vol.  xxxix.,  p.  31. 

5  •' Bothriocephalus- Anemie,"  Berlin,  1894. 

^Zeitschr.  f.  klin.  Med.,  1893,  vol.  xxiii.,  p.  80.    Ibid.,  1895,  vol.  xxvii.,  p.  492. 

^  Rivista  clin. ,  1889,  vol.  iv.,  p.  750. 


INTESTINAL    OBSTRUCTION.  35/ 

been  aptly  described  by  Ehrlich  ^  as  '*  a  pernicious  anemia,  with 
a  known  and  removable  cause."  It  is  distinguishable  from  true 
pernicious  anemia  solely  by  the  fact  that  after  the  expulsion  of 
the  worm  by  the  administration  of  appropriate  vermifuges  the 
megaloblastic  type  of  blood  and  the  anemia  rapidly  disappear,  and 
the  patient  makes  an  uneventful  recovery. 

The  anemia  of  ankylostomiasis,  while  it  may  reach  a  very  high 
grade  of  development,  still  does  not  counterfeit  pernicious  anemia. 
Griesinger's  "  Egyptian  chlorosis,"  the  brick-makers'  anemia  of  the 
Germans,  and  the  miners'  anemia  of  the  Italians,  as  well  as  many 
forms  of  tropical  anemia,  are  all  due  to  the  effects  of  this  nematode. 
The  hemoglobin  and  erythrocyte  loss  may  individually  be  as  great 
as  is  seen  in  Biermer's  disease,  but  low  color  indices  rule,  since 
the  former  is  more  strikingly  reduced  than  the  latter.  The  erythro- 
cytes are  commonly  found  in  a  state  of  marked  deformity,  both 
as  to  shape  and  size,  polychromatophilia  may  be  noted,  and  eryth- 
roblasts  are  often  seen,  but  never,  so  far  as  our  present  knowledge 
indicates,  is  there  a  prevalence  of  megaloblasts,  as  there  is  in  both 
bothriocephalus  and  in  pernicious  anemias. 

Leucocytosis  does  not  accompany  any  of  the 

Leucocytes,  above-named  forms  of  helminthiasis,  except  as 
the  effect  of  some  comphcation.  As  already 
pointed  out  (see  page  200),  a  conspicuous  feature  of  the  blood  is 
the  frequent,  but  not  constant,  occurrence  of  both  a  relative  and  an 
absolute  increase  in  the  percentage  of  eosinophiles.  The  eosino- 
philia  may  be  moderate  or  it  may  be  enormous — in  a  case  of  an- 
kylostomiasis reported  by  Ashford,^40  per  cent.,  or  a  total  count 
of  7,200  eosinophiles  to  the  cubic  millimeter  of  blood;  72  per 
cent,  in  a  case  of  the  same  disease  and  34  per  cent,  in  a  patient 
harboring  the  tenia  mediocanellata,  these  instances  having  been 
reported  by  Leichtenstern.^  Even  the  oxyuris  vermicularis,  al- 
though it  is  not  considered  to  be  a  factor  in  the  production  of 
anemia,  may  cause  a  well-marked  increase  in  the  percentage  of 
eosinophiles,  these  cells  sometimes  constituting  from  10  to  15  per 
cent,  of  all  forms  of  leucocytes. 

XXXIV.     INTESTINAL  OBSTRUCTION. 

The  hemoglobin  and  erythrocytes  are  unaffected,  except  in  ob- 
struction due  to  malignant  disease  or  associated  with  hemor- 
rhage, in  which  there  may  be  a  moderate  secondary  anemia. 

J  Loc.  cit. 

2N.  Y.  Med.  Journ.,  1900,  vol.  Ixxi.,  p.  552. 

3  Cited  by  Ehrlich  :    loc.  cit. 


358  GENERAL    HEMATOLOGY. 

Leiicocytosis  is  a  frequent,  though  not  a  constant,  accompani- 
ment of  all  forms  of  ileus,  even  those  with  comparatively  slight 
symptoms.  The  increase  is  most  constant  in  obstruction  de- 
pending upon  malignant  disease  or  complicated  by  gangrene  and 
peritonitis,  and  in  this  class  of  cases  it  tends  to  reach  the  highest 
figures,  except  in  the  event  of  grave  intoxication.  Bloodgood  ^ 
regards  the  presence  of  a  high  leucocytosis  (20,000  to  30,000)  on 
the  third  or  fourth  day  after  the  onset  of  symptoms  as  a  favorable 
indication  for  operative  interference,  but  he  considers  that  low 
counts  (below  10,000)  under  the  same  circumstances  indicate 
extensive  gangrene-peritonitis,  or  that  the  patient  will  be  so  de- 
pressed that  reaction  can  not  follow  reHef  of  the  obstruction. 

XXXV.      LEPROSY. 

The  studies  of  Winiarski,^  and  of  P.  K.  Brown, '^  show  that  in 
the  early  stages  of  this  disease  neither  the  Jiemoglobin  nor  the 
erythrocytes  suffer  any  deterioration,  but  that  in  advanced  leprosy, 
especially  in  cases  with  extensive  ulcerative  lesions,  the  anemia 
may  be  striking — quite  as  marked,  in  fact,  as  in  a  moderately 
severe  case  of  true  Biermer's  anemia.  In  such  instances  there  is 
a  conspicuous  oligocythemia  in  comparison  to  the  oligochro- 
memia,  and  the  counts  may  fall  to  below  2,000,000  to  the  cubic 
millimeter.  A  tendency  toward  megalocytosis,  and  high  color 
indices  has  been  observed,  the  index  in  some  counts  being  as 
high  as  1.7.  Polycythemia,  resulting  from  peripheral  stagnation, 
may  be  a  feature  of  some  cases.  The  number  oi  leucocytes  is  not 
increased,  but  a  relative  lymphocytosis  is  a  commonly-observed 
differential  change  affecting  these  cells. 

Both  Brown  ^  and  Streker"^  have  succeeded  in  demonstrating 
the  bacillus  leprce  in  the  circulating  blood  during  life.  These 
organisms,  as  a  rule,  were  found  to  be  enclosed  in  the  leucocytes, 
and,  more  rarely,  lay  free  in  the  plasma.  On  the  other  hand, 
Bibb  ^  failed  in  30  cases  to  find  the  bacillus  by  blood  culturing, 
although  he  obtained  positive  results  constantly  with  blood  as- 
pirated from  the  leprous  tubercles. 

The  serum  diagnosis  of  leprosy  has  not  yet  come  into  general 
clinical  use,  although  positive  clump  reactions  with  cultures  of 
the  leprosy  bacillus  and  the  serum  of  lepers  have  been  observed. 

^Am.  Med.,  I901,  vol.  i.,  p.  306. 

2  St.  Petersburg  nied.  Woch.,  1892,  vol.  ix.,  p.  365. 

3  Trans.  California  State  Med.  Soc,  1897,  vol.  xxvii.,  p.  168. 
*Munch   med.  Woch.,  1897,  vol.  xliv. ,  p.  1103. 

5  Am.  Journ.  of  Med.  Sc,  1894,  vol.  cviii.,  p.  539. 


MALARIAL    FEVER.  '  359 

XXXVI.    MALARIAL   FEVER. 

The  specific  cause  of  malarial  fever  is  a  form 
Parasitology,  of  blood  parasite  generally  known  as  the  plas- 
moditim  inalarice  or  the  heniameba  malarice,  an 
organism  classified  among  the  Sporozoa,  according  to  Metchni- 
koff  ^  First  accurately  described  in  1880,  by  Laveran,^  a  medical 
officer  of  the  French  army,  stationed  in  Algeria,  our  knowledge 
of  the  parasite  and  its  relation  to  the  malarial  fevers  has  been 
furthered  chiefly  by  the  researches  of  Richard,^  also  a  French 
army  surgeon  ;  of  Grassi  and  Filetti,*  in  Sicily  ;  of  Mannaberg,^ 
in  Austria;  of  Marchiafava  and  Celli,^  Bastianelli  and  Bignami,^  and 
Golgi,^  of  the  Italian  school;  and  of  Councilman  and  Abbott,^  Stern- 
berg,^°  Osler,^^  Dock,^^  and  Thayer  and  Hewetson,^^  in  America. 
In  addition  to  these  principal  investigators,  numerous  workers  in 
other  parts  of  the  world  have  materially  advanced  our  knowledge 
of  the  subject/"^ 

Developmerital  Cycle  in  Man.  The  malarial  organism  gains 
entrance  to  the  erythrocyte  of  man,  in  which  it  pursues  a  definite 
cycle  of  development,  at  the  expense  of  its  corpuscular  host. 
Existing  in  its  earliest  stages  as  a  hyaline,  ameboid  body  within 
the  substance  of  the  corpuscle,  the  parasite  increases  in  size,  and 
derives  fine  pigment  granules  from  the  hemoglobin  of  its  host, 
which  it  ultimately  destroys  at  the  time  its  full  maturity  is  attained. 
Full  development  of  the  parasite  having  been  reached,  it  divides 
into  a  number  of  segments,  which,  by  the  rupture  of  the  blood 
cell,  are  set  free  to  enter  fresh,  uninvaded  erythrocytes  and  there 

iCentralbl,  f.  Bakt.  u.  Parasit.,  1887,  vol.  i.,  p.  624. 

2  "  Nature  parasitaire  des  accidents  de  I'impaludisme,"  Paris,  1881. 

3Gaz.  med.  d.  Paris,  1882,  vol,  iv.,  p.  252. 

^Centralbl.  f.  Bakt.  u.  Parasit.,  1890,  vol.  vii.,  pp.  396  and  430.  Ibid.,  1891,  vol. 
ix.,  pp.  403,  429,  and  461.     Ibid.,  vol.  x.,  p.  449. 

5  "  The  Malarial  Parasites,"  New  Sydenham  Soc.  Transl.,  London,  1894,  vol.  cl., 
p.  241. 

^Forschr.  d.  Med.,  1885,  vol.  iii.,  p.  787,  Ibid.,  1888,  vol.  vi.,  p.  450.  Also 
Festchr.  z.  Virchow's  70.  Geburtstag,  1891,  vol.  iii.,  p.  187. 

''Riforma  med.,  1890,  vol.  vi.,  pp.  860,  866,  and  872.  Also  Lancet,  1898,  vol. 
ii.,  p.  1461, 

8  Archiv.  per  le  sc.  med.,  1886,  vol.  x.,  p.  109. 

9  Am.  Journ.  of  Med.  Sc,  1885,  vol.  Ixxxix.,  p.  416.  Also  Med.  News,  1887, 
vol.  i.,  p.  59. 

'°Med.  Record,  1886,  vol.  xxix.,pp.  489  and  517. 

JiPhila.  Med.  Times,  1886,  vol.  xvii.,  p.  126. 

12 Med.  News,  1890,  vol.  Ivii.,  p.  59.     Ibid.,  1891,  vol.  Iviii.,  pp.  602  and  628. 

^3  Johns  Hopkins  Hosp.  Reports,  1895,  vol.  v.,  p.  3. 

^*  For  an  exhaustive  bibliography  the  reader  should  consult  Thayer's  admirable 
monograph,  "Lectures  on  the  Malarial  Fevers,"  N.  Y.,  1897.  An  authoritative 
account  of  the  malarial  fevers  in  all  their  phases  is  given  in  Celli's  book,  "  Malaria 
According  to  the  New  Researches,"  English  translation  by  J.  J.  Eyre.  London  and 
N.  Y.,  1900. 


360  GENERAL    HEMATOLOGY. 

to  initiate  a  new  developmental  cycle  of  similar  characteristics. 
Segmentation  or  sporulation  of  a  group  of  parasites  is  accompa- 
nied by  a  paroxysm,  which  is  in  all  probability  due  to  the  influ- 
ence of  certain  toxic  material  liberated  at  this  time. 

But  in  order  to  complete  its  full  life  cycle,  the  malarial  parasite 
must  also  pass  through  a  developmental  phase  within  the  bodies 
of  certain  mosquitoes,  for  it  has  been  shown  that  these  insects  not 
only  act  as  the  intermediate  hosts  of  the  parasite,  but  also  cany 
the  infection  by  means  of  their  bite.  These  important  discoveries 
were  first  made  by  Ross,^  whose  conclusions  were  shortly  con- 
firmed by  Grassi,  Bignami,  and  Bastianelli,^  and  by  others  of 
the  ItaHan  school. 

Developmental  Cycle  in  the  Mosquito.  While  in  the  human 
body  the  malarial  parasite  pursues  an  asexual  cycle,  terminating 
in  segmentation,  in  the  body  of  mosquitoes  of  the  genus  Anopheles 
it  follows  out  a  true  sexual  cycle.  In  the  blood  of  man  certain 
of  the  parasites  which  do  not  undergo  segmentation,  constitute 
sexual  forms  of  the  organism,  known  as  gametes,  which,  after 
having  been  imbibed  by  the  mosquito  while  biting  a  malarious 
individual,  develop  into  impregnated  bodies  by  reason  of  the  fe- 
cundation of  the  female  sexual  elements,  or  7nacroganietes,  by  the 
free  flagella,  or  microgainetes,  which  have  become  detached  from 
the  male  sexual  elements,  or  microgametocytes.  The  resultant 
fertilized  bodies  develop  into  motile  pseudo-verjnicules,  which, 
having  penetrated  the  muscular  wall  of  the  mosquito's  stomach, 
lodge  and  become  encysted  in  this  situation  and  are  now  known 
as  zygotes.  From  the  latter  are  derived  large  numbers  of  delicate 
spindle-shaped  cells,  or  sporoblasts,  which,  by  the  rupture  of  the 
zygote' s  capsule,  are  set  free,  and,  as  sporozoids^  make  their  way 
into  the  salivary  gland  of  their  host,  whence  they  pass  by  way  of 
the  salivary  duct  into  the  proboscis  of  the  insect,  and  conse- 
quently into  the  circulating  blood  of  the  individual  stung  by  the 
infected  mosquito.  The  sporozoids  thus  inoculated  into  the  blood 
of  man,  penetrate  his  erythrocytes,  in  which,  as  the  young  hyaline 
forms  of  the  malarial  parasite,  they  pursue  the  typical  develop- 
mental cycle  to  be  described  below. 

Thus,  it  has  been  definitely  shown  that  mosquitoes  of  the  genus 
Anopheles  are  capable  of  transmitting  malarial  infection  from  man 
to  man,  and  it  is  now  generally  believed  that  this,  the  only  proven 
method  of  malaria  transmission,  is  probably  the  sole  means  by 

1  "  Report  on  the  Cultivation  of  Proteosoma  (Labb6)  in  Gray  Mosquitoes."  Cal- 
cutta, 1898. 

*  Reals  Accademia  dei  Lincei.  Estratto  dal,  vol.  vii.,  2°  sem.,  ser.  5a.,  fasc.  11°. 
Seduta  del  4  dicembre,  1898.  Abst.  in  Progressive  Med.,  Phila.,  1899,  vol.  i.,  p. 
287.  See  also  Bignami,  Lancet,  1898,  vol.  ii.,  pp.  1461  and  1541.  Grassi,  II 
Policlinico,  1898,  vol.  v.,  p.  469. 


p. 


p. 


v 


SINGLE  TERTIAX  IXFECTIOX. 
Paroxysm  every  third  day. 

R  P.  P. 

*  *  * 


10 


P. 


11 


CHART    III, 


P. 


\r 

12       13 


p. 


DOUBLE  TERTIAN  IXFECTIOX. 

Daily  paroxysm. 

p.         P.         p.        P.         P.         P.        P. 


V 


V 


V 


^ 


\^ 


10 


11 


V 


12 


SINGLE  QUARTAN  INFECTION. 

Paroxysm  every  fourth  day. 

P.  P.  P. 

*  *  * 


P. 

* 


10 


11 


12 


13 


P. 
* 


DOUBLE  QUARTAN  INFECTION. 
Paroxysm  on  t\\-o  successive  days  willi  one  day's  intermission. 
P.  P.        P.  P.         P.  P.         P. 


■f 


V 


^ 


10 


V 


11 


12        13 


P. 


y= 


14 


P. 

* 


P. 


^=^ 


TRIPLE  QUARTAN  INFECTION. 

Daily  paroxysm. 

P.         P.         P.        P.         P.        P.         P. 


\^V^ 


y~V   V — ^^^ 


6 


S  9  10         11         12 


CHART  ILLUSTRATING  THE  DIFFERENT  TYPES  OF  FEVER 
RESULTING  FROM  INFECTION  WITH  SINGLE  AND  WITH 
MULTIPLE    GROUPS   OF    MALARIAL    PARASITES. 

The  duration  of  the  parasites'  cycle  of  development 
is  expressed  by  colored  lines,  thus: 

Black:  First     group  of  parasites. 

Red:  Second     "  "         '     " 

Blue:  Third        "  "        "     " 

P:  Paroxysm. 


MALARIAL    FEVER.  36 1 

which  the  disease  is  spread.  The  ordinary  house-mosquito,  of 
the  genus  Ciilex,  is  not  concerned  in  the  transmission  of  malaria, 
since  it  has  been  proved  that  the  parasites  do  not  follow  out  a 
developmental  cycle  within  the  body  of  this  insect. 

For  a  complete  review  of  the  ''mosquito  theory"  of  malaria, 
embracing  the  recent  work  of  Ross,  Manson,  MacCallum,  and 
the  Italian  school,  the  reader  should  consult  Thayer's  **  Recent 
Advances  in  our  Knowledge  Concerning  the  Etiology  of  Malarial 
Fever,"  ^  Futcher's  "A  Critical  Summary  of  Recent  Literature 
Concerning  the  Mosquito  as  an  Agent  in  the  Transmission  of 
Malaria,"  ^  and  Howard's  "  Mosquitoes." 

Varieties  of  the  Malarial  Parasite.  Three  distinct  varieties  of 
the  parasite  are  recognized,  each  of  which  has  been  found  con- 
stantly associated  with  a  specific  type  of  malarial  infection.  These 
three  varieties  are  : 

1.  The  parasite  of  tertian  fever ^  associated  with  a  regularly 
intermittent  type  of  fever,  with  paroxysms  every  third  day. 

2.  The  parasite  of  quartan  fever,  associated  with  a  regularly 
intermittent  type  of  fever,  with  paroxysms  every  fourth  day. 

3.  TJie  parasite  of  estivo-autumnal  fever,  associated  with  the 
more  irregular  types  of  fever. 

The  parasites  of  tertian  and  of  quartan  fever  exist  in  the  blood 
of  the  infected  individual  in  great  groups  consisting  of  immense 
numbers  of  organisms  all  of  which  are  approximately  at  the  same 
stage  of  development,  and  therefore  undergo  sporulation  at  about 
the  same  period.  This  fact  serves  to  explain  the  regularity  of 
the  tertain  and  quartan  paroxysms.  On  the  other  hand,  in  estivo- 
autumnal  infections  this  regular  grouping  of  the  parasites  is  often 
wanting,  and  large  numbers  of  this  organism  commonly  exist  in 
the  blood  in  different  stages  of  development.  Sporulation  thus 
taking  place  at  irregular  intervals,  irregularity  in  the  occurrence 
of  the  estivo-autumnal  paroxysms  is  extremely  common. 

As  the  development  of  these  three  types  of  the  malarial  para- 
site progresses,  certain  forms  are  evolved  which  possess  more 
or  less  common  characteristics,  so  that  it  is  convenient  to  speak 
of  these  forms,  which  represent  the  maturing  phases  of  the  or- 
ganism, as  follows  : 

(^)  The  intracellular  hyaline  forms. 

(^)  The  pigmented  intracellular  forms. 

(  ^  )  The  pigmented  extracellular  forms. 

(^)  The  segmenting  forms. 

(  ^)  The  flagellate  forms. 

1  Proc.  Phila.  Co.  Med.  Soc. ,  1900,  vol.  xxi.,  p.  211. 

2  Am.  Journ.  of  Med.  Sc,  1899,  vol.  cxviii.,  p.  318. 


362  GENERAL    HEMATOLOGY. 

Furthermore,  in  parasites  of  the  estivo-autumnal  type  addi- 
tional forms,  those  of  the  crescent  group,  are  met  with,  these 
varieties  being  pecuhar  to  this  type  of  infection,  and  never  occur- 
ring in  tertian  and  quartan  fevers. 

Tertian  infections  constitute  the  prevailing  type  of  malarial 
fever  in  almost  all  countries  in  which  the  disease  exists.  Quartan 
fevers  are  relatively  uncommon,  except  in  certain  hmited  districts, 
parts  of  Sicily,  for  example,  in  which  a  large  proportion  of  the 
cases  conform  to  this  type.  Estiv^o-autumnal  fevers  are  especially 
common  in  the  tropics,  but  this  type  of  the  disease  is  by  no  means 
incompatible  with  temperate  regions.  In  Philadelphia  and  its  en- 
virons tertian  infections  are  about  five  times  as  common  as  those 
of  the  estivo-autumnal  type,  while  quartan  malaria  is  practically 
unknown.  The  writer  has  seen  but  a  single  instance  of  quartan 
infection  in  this  vicinity,  and  this  case  was  without  doubt  imported. 

The  Parasite  of  Tertian  Fever.  (Plate  VI . )  The  tertian  parasite 
attains  its  full  development  in  about  forty-eight  hours,  segmenta- 
tion of  a  single  group  of  organisms  at  this  interval  producing  the 
characteristic  paroxysms  every  third  day.  Infection  with  two  dis- 
tinct groups  of  parasites,  each  maturing  on  successive  days,  gives 
rise  to  a  quotidian  type  of  fever,  characterized  by  the  occurrence  of 
daily  paroxysms.  (See  Chart  III.,  p.  361.)  Infection  with  more 
than  two  groups  is  extremely  rare,  and  produces  an  atypical  and 
irregular  type  of  fev^er. 

Anticipation  of  the  paroxysm,  which  is  especially  frequent  in 
tertian  fever,  may  be  explained  by  a  precocity  displayed  by  a 
group  of  parasites,  by  virtue  of  which  their  development  is  so 
rapid  that  the  stage  of  sporulation  is  reached  before  the  expira- 
tion of  forty-eight  hours.  On  the  contrary,  should  the  develop- 
ment of  a  group  happen  to  be  slower,  requiring  more  than  forty- 
eight  hours  for  its  full  maturity  and  sporulation,  then  the  paroxysm 
is  retarded. 

If  a  specimen  of  fresh,  unstained  blood  from  a  case  of  tertian 
fever  is  examined  during  the  period  immediately  or  shortly  fol- 
lowing the  malarial  paroxysm,  it  will  be  observed  that  many  of 
the  erythrocytes  contain  small,  pale,  transparent,  foreign  bodies, 
dim  of  outline,  more  or  less  markedly  ameboid  in  character,  and 
of  a  peculiar  dirty,  grayish-pearl  tint.  These  bodies,  known  as 
the  intracellular  hyaline  forms,  represent  the  youngest  forms 
of  this  organism,  being  derived  from  the  sporulation  of  the  im- 
mediately preceding  group  of  parasites.  They  may  occasionally 
be  found  in  the  peripheral  blood  toward  the  latter  part  of  the 
paroxysm,  and  for  a  short  time  after  the  occurrence  of  this 
phenomenon. 


PLATE  VI. 


■■'■•v^?' 


10 


11 


12 


■.;• » 
13 


14 


15 


16 


The  Tertian  Parasite. 


1.  Normal  erythrocyte. 

2,  3,  4,  5.    Intracellular  hyaline  forms. 

6,  7.  yoiuig  pigviented  intracellular  forms.  In  6  two  distinct  parasites  inhabit  the  ery- 
throcyte, the  larger  one  being  actively  ameboid,  as  evidenced  by  the  long  tentacular 
process  trailing  from  the  main  body  of  the  organism.  This  ameboid  tendency  is 
still  better  illustrated  in  7,  by  the  ribbon-like  design  formed  by  the  parasite.  Note 
the  delicacy  of  the  pigment  granules,  and  their  tendency  toward  peripheral  arrange- 
ment in  6,  7,  and  8. 

8.  Later  develofimental  stage  of  7.     In  7,  8,  and  9  enlargement  and  pallor  of  the  infected 

erythrocyte  become  conspicuous. 

9.  Mature  intracellular  pigmented  parasite. 

ID,  II,  12.  .'Segmenting  forms.  In  10  is  shown  the  early  stage  of  sporulation — the  develop- 
ment of  radial  striatiotis  and  peripheral  indentations  coincidentally  with  the  swarm- 
ing of  the  pigment  toward  the  center  of  the  parasite.  The  completion  of  this  process 
is  illustrated  bv  11  and  12. 

13.  Large  sivollen  extracellular  form.      Note  the  coarse  fused  blocks  of  pigment.     (Com- 

pare size  with  that  of  normal  erythrocyte,  i.) 

14.  Flagellate  form. 

IS-  Shrunken  and  fragmenting  extracellular  forms. 
16.    Vacuolation  of  an  extracellular  form. 

Note. — The  original  water-color   drawings  were  made  from   fresh  blood   specimens,  a 
Leilz  x2-iiich  oil-immersion  objective  and  4  ocular,  with  a  Zeiss  camera-Iucida,  being  used. 

(E.  F,  Fabkr, /<?/:.) 


MALARIAL    FEVER.  3^3 

The  ameboid  movements  of  these  hyaline  bodies  form  one  of 
their  most  striking  features,  and  in  consequence  of  this  trait  their 
shape  is   constantly  altered.     At  one   moment  the  parasite  ap- 
pears as  a  flattened  spherical  or  oval  disc,  measuring  2  or  3  /i  m 
diameter;  the  next  Instant  it  may  change  to  the  shape  of  a  jack- 
stone,  or'become  a  stellate  design,  or  take  the  form  of  an  anvil. 
The  succession  of  figures  which  the  organism  may  resemble  is 
limitless.     As  the  parasite  increases  In  size,  long  pseudopodia, 
like  the  delicate  tendrils  of  a  vine,  are  alternately  thrown  out 
and  retracted,  reaching  here  and  there  through  the  corpuscular 
substance  with  uncertain  but  sudden  motility.    In  the  active  par- 
asite   these    pseudopodia    appear   as    long,   delicate,   gracefully 
curved  branchings  of  the  protoplasm,  usually  terminating  In  a 
spherical    knob-nke    extremity,   and    measuring    4    or   5    //   in 
length,  in  many  Instances.     Occasionally  the  parasite  seems  to 
have  formed  a  perfect  ring,  either  because  of  the  thinning  out  of 
Its  central  portion,  or,  rarely,  by  reason  of  the  fusion  of  two  short 
pseudopodia  between  which  a  small   portion  of  the  corpuscle 
becomes  Imprisoned.     The  outline  and  color  of  the  hyaline  body 
are  quite  characteristic,  at  least  to  the  eye  of  the  practised  ob- 
server.    Usually  described  as  quite  colorless,  the  parasite  rather 
possesses  a  distinctive  pearly  tint,  overlaid  In  patches  by  layers 
of  corpuscular  substance  of  varying  depth,  so  that  In  certam  hghts 
the  yellowish-green  color  of  the  erythrocyte  predominates,  and  ob- 
scures the  true  color  of  the  organism  to  some  extent.   Usually  but  a 
single  hyaline  body,  situated  somewhat  eccentrically.  Is  found  m 
the^'corpuscle  ;  less  commonly,  two  or  more  are  harbored. 

The  next  stage  in  the  development  of  the  organism,  the  col- 
lection of  pigment  granules  derived  from  hemoglobin  of  the 
erythrocyte,  is  reached  toward  the  latter  part  of  the  first  twenty- 
four  hours  following  the  paroxysm.  By  this  time  the  size  of  the 
parasite  has  increased  to  about  half  that  of  Its  corpuscular  host, 
and  It  Is  now  known  as  an  intracellular  pigmented  form. 

The  pigment  appears  as  a  collection  of  exceedingly  fine,  yel- 
lowish-brown granules  which  are  usually  most  densely  distributed 
near  the  peripheral  rather  than  the  central  portion  of  the  parasite. 
In  the  large  spherical  forms  of  the  latter,  most  of  the  pigment  is 
arranged  In  a  series  of  irregular  clumps,  loosely  strung  together 
by  delicate,  wavy  connecting  lines  consisting  of  Individual  gran- 
ules ;  or  the  rim  of  the  parasite  may  be  paralleled  for  the  greater 
part  of  its  extent  by  a  pigment  design  not  unlike  a  wreath  or  a 
hoop.  The  individual  granules  are  observed  to  be  in  active,  in- 
cessant motion,  their  violent  oscillations  hither  and  thither  form- 
ino-  a  olcture  that  at  once  arrests  the  attention  of  the  observer. 


364  GENERAL    HEMATOLOGY, 

In  many  of  the  ameboid  figures,  a  polar  distribution  of  the  pig- 
ment is  noticeable,  the  greater  part  of  the  granules  being  situated, 
in  fine  clumps,  in  the  knob-like  extremities  of  the  several  pseudo- 
podia  ;  and  even  in  these  situations  the  typical  tendency  of  the 
pigment  to  arrange  itself  eccentrically,  is  striking. 

As  the  parasite  matures,  it  becomes  of  still  larger  size,  more 
and  more  pigmented,  and  less  and  less  ameboid,  the  latter  char- 
acteristic becoming  quite  or  almost  entirely  lost  by  the  time  it 
attains  its  full  growth.  The  pigment,  fine,  of  yellowish-brown 
color,  and  eccentrically  distributed  in  the  earlier  forms,  is  at  this 
period  of  the  organism's  growth  much  coarser,  darker  in  color, 
and  more  scattered  throughout  the  protoplasm.  Some  of  the 
granules  are  fused  into  minute,  dark-colored  spikes  and  rods,  in 
contrast  to  the  discrete,  dot-like  granules  of  the  younger  parasites. 

Coincidentally  with  these  changes,  striking  alterations  are  ap- 
parent in  the  invaded  erythrocytes.  These  cells  become  pro- 
gressively paler  and  more  sw^ollen  as  the  development  of  the  para- 
site goes  on,  until  at  the  time  of  the  latter' s  full  maturity  (attained 
after  a  growth  of  about  forty  hours'  duration)  the  corpuscles 
have  become  almost  entirely  decolorized,  and  appear  now  as  hya- 
line or  pale  yellowish  rims  encircling  the  parasite,  the  size  of  which 
is  now  approximately  equal  to  that  of  a  normal  erythrocyte. 

Just  before  and  during  the  next  paroxysm,  or  from  about  forty 
to  forty-eight  hours  after  the  preceding  chill,  the  parasite  attains 
its  full  maturity,  and  the  stage  of  sporulation  occurs.  Coinci- 
dentally with  this,  segmenting  f onus  of  the  parasite  begin  to  appear 
in  the  blood.  In  tertian  infections  segmentation  occurs  to  a 
greater  extent  in  the  deep  than  in  the  peripheral  circulation,  but 
if  finger  blood  is  obtained  two  or  three  hours  before  the  chill,  a 
few  *'  segmenters  "  will  almost  always  be  found,  if  the  search 
for  them  is  careful  and  thorough.  In  cases  in  w^hich  the  number 
of  parasites  has  been  scanty^  during  the  preceding  days  of  the  at- 
tack, it  may  be  impossible  to  detect  these  forms,  in  spite  of  careful, 
skilled  obsei-vation. 

Segmentation  is  heralded  by  a  tendency  of  the  pigment  gran- 
ules to  collect  in  or  near  the  center  of  the  parasite,  in  one  large 
or  in  several  smaller  compact  clumps,  or  fused  masses.  This 
having  taken  place,  a  number  of  minute,  somewhat  refractive 
points  may  be  seen  with  more  or  less  distinctness,  the  majorit}' 
of  these  spots  being  confined  to  the  peripheral  portion  of  the  organ-, 
ism,  which  by  this  time  has  lost  a  great  deal  of  its  earlier  clear, 
hyaline  appearance,  and  has  become  dully  opaque,  and  somew^hat 
granular.  Following  the  development  of  these  refractive  points, 
indistinct    parallel    linear    shadings,  usually  fifteen  or  twenty  in 


MALARIAL    FEVER.  365 

number,  extending  from  the  periphery  of  the  parasite  toward  the 
central  collection  of  pigment,  may  be  discerned  ;  and  coincidentally 
with  this  change  the  rim  of  the  parasite  becomes  wrinkled,  then 
distinctly  corrugated,  each  corrugation  capping  a  pair  of  these 
radiating  shadings.  The  latter  finally  become  the  dividing  lines 
of  fifteen  or  twenty  spores  or  segments,  of  somewhat  round  or 
ovoid  shape,  radiating  in  an  irregular  figure  toward  the  central 
pigment  mass.  By  careful  focusing,  each  segment  is  found  to 
contain  a  central  refractive  spot,  the  whole  collection  being  sur- 
rounded and  held  together  by  the  shell  of  the  erythrocyte,  now 
so  decolorized  that  it  is  scarcely  visible. 

Finally,  when  segmentation  is  completed,  the  spores,  for  as  such 
these  segmenting  bodies  must  now  be  considered,  are  freed  from 
the  body  of  the  corpuscle  which  has  served  until  this  time  as 
their  limiting  capsule.  The  latter  having  apparently  ruptured, 
the  spores  escape,  either  by  gradually  emerging  several  at  a  time, 
or  by  the  simultaneous  and  extremely  abrupt  exit  of  their  whole 
number.  The  spores,  which  now  lie  free  in  the  blood  plasma, 
surround  the  remains  of  the  central  pigment  mass  in  an  irreg- 
ular group,  which  has  been  likened  in  appearance  to  a  bunch  of 
grapes.  Sooner  or  later  they  wander  off  through  the  plasma  and 
disappear  from  view,  the  inference  being  that  they  invade  fresh 
erythrocytes  and  thus  initiate  a  new  cycle  of  development  of 
another  forty-eight  hours'  duration.  Although  visual  proof  of 
this  invasion  is  lacking,  the  fact  that  hyaline  bodies,  biologically 
similar  to  these  free  spores,  are  found  in  the  erythrocytes  at  or 
shortly  after  the  time  of  segmentation,  must  be  regarded  as  suf- 
ficiently strong  evidence  of  the  truth  of  this  inference.  Most  of 
the  liberated  pigment  is  carried  off  through  the  blood,  to  be  de- 
posited in  various  organs,  while  some  of  it  is  taken  up  by  phago- 
cytes. 

The  preceding  remarks  refer  to  the  typical  cycle  of  the  par- 
asite's development,  from  the  smallest  hyaline  intracellular  body 
to  the  full-grown  pigmented  segmenting  variety,  from  which  the 
former  is  derived.  But  all  the  parasites  of  one  group  do  not 
pursue  this  routine,  some  escaping  prematurely  from  the  eryth- 
rocyte at  an  early  period  of  their  life  history,  others  continuing 
to  develop  further,  and  losing  their  corpuscular  capsule  just  prior 
to  the  time  segmentation  begins  in  the  other  parasites  of  the 
same  group.  In  consequence  of  these  changes,  another  distinct 
class  of  tertian  parasites,  the  extracellular  pigmented  forms,  is  pro- 
duced, and  it  is  the  varieties  of  this  class  that  we  now  have  to 
consider. 

In  the  first  instance,  the  young,   slightly  pigmented  parasite 


366  GENERAL    HEMATOLOGY. 

escapes  from  its  corpuscular  host  through  an  apparent  breach  in 
the  surface  of  the  latter.  The  immediate  effect  of  its  contact 
with  the  blood  plasma  is  to  convert  it  into  a  deformed,  dwarfed 
body  of  protoplasm,  which  sooner  or  later  becomes  wholly  de- 
void of  ameboid  motion.  It  is  often  fragmented,  and  divided  into 
two  or  more  small  rounded  masses,  each  containing  an  amount 
of  pigment  seemingly  disproportionate  to  its  size,  compared  to 
the  quantity  found  in  the  intracellular  forms.  Sometimes  two  of 
these  pigmented  spheres  are  joined  to  one  another  by  a  filmy  con- 
necting thread  of  protoplasm,  from  3  to  5  a  in  length,  forming  a 
design  which  may  be  compared  to  a  miniature  chain-shot.  After 
the  lapse  of  a  short  length  of  time,  the  outlines  of  these  bastard 
forms  of  the  parasite  become  almost  indistinguishable.  The  eryth- 
rocytes from  which  they  have  escaped  become  completely  decolor- 
ized and  invisible  shortly  after  this  accident  has  occurred. 

In  the  second  instance,  in  which  the  parasite  loses  its  corpus- 
cular envelope  just  before  the  time  of  segmentation,  the  resulting 
spherical  extracellular  body  is  usually  of  large  size,  often  9  to 
12  /i  in  its  greatest  diameter,  or,  in  the  smaller  forms,  about  the 
size  of  the  normal  red  cell.  It  is  filled  with  actively  moving  pig- 
ment granules,  arranged  eith^  peripherally,  or  scattered  through- 
out its  body,  and  standing  out  in  bold  relief  against  the  back- 
ground formed  by  the  pale  surface  of  the  parasite.  The  granules 
in  this  form  of  the  organism  are  usually  quite  dark  in  color,  some 
of  them  being  welded  and  fused  into  minute  spiculate  figures, 
while  others  remain  free  and  distinct. 

These  extracellular  pigmented  bodies  are  of  especial  interest, 
for  the  reason  that  from  them  develop  those  most  striking  varie- 
ties of  the  malarial  parasite,  the  flagellate  forms.  The  earliest 
evidence  of  the  process  of  flagellation  is  seen  in  the  strikingly 
increased  activity  of  the  pigment,  the  oscillations  of  the  granules 
growing  more  and  more  violent  with  the  approach  of  the  phe- 
nomenon. Then,  one  or  more  long,  almost  transparent  tentacular 
processes  are  observed  suddenly  to  burst  from  the  periphery  of 
the  parasite,  their  violent  and  incessant  whipping  about  in  the 
plasma  causing  more  or  less  disturbance  of  the  blood  corpuscles 
in  their  vicinity.  The  pigment  granules,  meanwhile,  have 
swarmed  together  into  a  loose  mass  at  or  near  the  center  of  the 
main  body.  The  length  of  the  flagella  varies  from  4  to  5  to  20 
/z  or  longer,  their  average  breadth  being  somewhat  less  than  .5 
/i.  They  frequently  possess  one  or  more  bulbous  swellings, 
usually  at  their  distal  extremity,  occasionally  at  their  proximal 
end,  and  also  at  other  points  along  their  course  intermediate  to 
these   situations.     They  may  or  may  not  contain  a  few  fine  and 


PLATE  VII. 


'"\ 


9®  0 


10  11 


J,"  V  % 


14   U'V.---^ 


The  Quartan  Parasite. 


1.  Normal  erythrocyte. 

2.  Ivtraccl/uiar  hyalhie  form. 

3.  Yuung  pig-tnetited  intracellular  fortn.     Note  the  coarseness,  dark  color,  and  scantiness 

of  the  pip:iiient  granules. 

4.  5,  6,  7.   Later  developmental  sta^^es  o/".?.     Note  the  peripheral  distribution  of  the  pigment 

in  all  the  parasites  from  3  to  8.     (Compare  size  and  color  of  the  erythrocytes  in  5,  6, 
and  7  with  7,  8,  and  9,  Plate  VI.) 

8.  Mature    intracellular  fortn.      Note   that    the   stroma  of   the  erythrocyte   is   no   longer 

demonstrable. 

9,  10,  II.   Segmenting^  forms.     In  9  are  shown  the  characteristic  radiating  lines  of  pigment. 

(Compare  with  10,  11,  and  12,  Plate  VI,  and  with  10,  ir,  and  12,  Plate  VIII.) 

12.  Large  s7vollen  extracellular  form.     (Compare  with  13,  Plate  VI.) 

13.  Flagellate  form.     (Compare  with  14,  Plate  VI.) 

14.  Vacuolation  of  an  extracellular  form. 

(E.   F.  FABER,y<?c.) 


MALARIAL    FEVER.  36/ 

active  dotlets  of  pigment  situated  in  the  swollen  extremity,  or 
sprinkled  as  fine  stipplings  along  their  course. 

The  ultimate  disposition  of  the  flagella  occurs  in  one  of  two 
ways  :  they  either  become  detached  from  the  large  spherical 
parasite,  and,  as  free  flagella,  wander  off  through  the  plasma, 
propelled  by  their  own  ameboid  movements,  which  finally  cease, 
after  which  they  soon  disappear  from  view  ;  or,  remaining  attached 
to  the  large  body,  they  are  observed  to  disappear  by  apparently 
reentering  the  large  parasite  and  becoming  reincorporated  with 
its  protoplasm.  Flagellate  forms  do  not  occur  in  the  circulating 
blood,  and  are  not  found  in  the  fresh  specimen  until  some  little 
time,  usually  from  ten  to  twenty  minutes,  has  elapsed  after  the 
withdrawal  of  the  blood  from  the  body.  They  are  most  easily 
found  in  blood  which  has  been  taken  from  the  patient  just  before 
the  onset  of  a  paroxysm.  The  nature  and  functions  of  these 
flagellate  bodies  were  first  clearly  determined  by  MacCallum,^ 
who  proved  that  the  flagella  are  true  male  sexual  organs,  actively 
concerned  in  the  process  of  fertilization,  to  which  reference  has 
already  been  made.     (See  page  360.) 

Some  of  the  extracellular  bodies,  failing  to  develop  flagella, 
undergo  vacuolization,  often  become  exceedingly  misshapen,  and 
sometimes  fragmented,  these  changes  being  regarded  as  degenera- 
tive in  character.  A  parasite  thus  affected  loses  its  regularly 
spherical  outline,  and  may  so  alter  in  appearance  that  it  resembles 
a  gourd,  or  a  partly  inflated  balloon.  Constrictions  at  one  or 
more  points  may  appear,  and  in  the  little  knobs  thus  cut  off  from 
the  main  body  of  the  organism,  a  few  actively  motile  pigment 
granules  are  usually  imprisoned.  Small  portions  of  the  original 
body,  containing  active  pigment,  may  become  extruded  and  float 
off  through  the  plasma,  but  sooner  or  later  the  pigment  in  these 
fragmented  bits  loses  its  motility  and  the  bodies  themselves 
become  deformed  and  so  indistinct  of  outline  that  they  are  lost 
to  view.  These  degenerative  forms  closely  resemble  those  de- 
rived from  prematurely-escaped  intracellular  parasites,  except 
that  the  latter,  as  a  rule,  contain  finer  and  less  abundant  pigment. 

2.  The  Parasite  of  Quartan  Fever.  (Plate  VII.)  The  quartan 
parasite  completes  its  cycle  of  development  in  about  seventy-two 
hours,  thus  producing  a  paroxysm  every  fourth  day.  Infection 
with  two  separate  groups  of  parasites  is  marked  clinically  by  a 
paroxysm  occurring  on  each  of  two  successive  days,  separated  by 
one  day  of  intermission.  Infection  with  three  groups  of  parasites 
produces  daily  paroxysms,  the  resulting  quotidian  type  of  fever 

1  Journ.  of  Exper.  Med.,  1898,  vol.  iii.,  p.  117.  Also,  Johns  Hopkins  Hosp. 
Bull.,  1897,  vol.  viii.,  p.  236. 


368  GENERAL    HEMATOLOGY. 

being  similar  to  that  due  to  double  tertian  infections.  (See  Chart 
III,  page  361.) 

Ordinarily,  the  quartan  parasite's  cycle  of  development  is  ex- 
tremely regular,  the  period  required  for  its  maturation  seldom 
deviating  from  seventy-two  hours.  It  is  owing  to  this  that  antici- 
pation and  retardation  of  the  paroxysm,  so  common  in  tertian  in- 
fections, are  rare  in  the  quartan  types  of  fever. 

The  young  hyaline  forms  of  the  quartan  parasite  closely  re- 
semble those  of  the  tertian  organism  ;  they  have  the  same  hyaline 
appearance,  the  same  indistinct  outline,  and  the  same  sort  of 
ameboid  movement.  While  the  quartan  hyaline  body  is 
usually  described  as  being  of  smaller  size  and  less  ameboid  than 
the  similar  tertian  form,  these  differences  are  not  well  enough 
marked  to  be  of  practical  application.  At  this  stage  of  its  life 
histor}',  the  organism  of  quartan  fever  possesses  no  distinctive 
characteristics  by  which  it  may  be  differentiated  from  the  tertian 
variety  of  a  similar  period  of  growth.  It  is  not  until  it  has  matured 
to  the  stage  of  pigmentation  that  it  is  possible  to  discern  points 
of  distinction  by  which  its  identity  may  be  fixed — characteristics 
which  become  more  and  more  striking  as  development  of  the 
parasite  progresses,  and  which  relate  to  its  color,  outline,  pigment, 
and  ameboid  powers,  as  well  as  to  changes  affecting  its  corpus- 
cular host. 

The  outline  of  the  pigmented  intracelbilar  form  is  much  more 
distinct  than  that  of  the  tertian,  its  margins  contrasting  rather 
than  blending  with  the  color  of  the  surrounding  erythrocyte. 
The  appearance  of  its  protoplasm  is  also  quite  different,  being  ap- 
parently denser  in  consistence,  more  highly  refractive,  and  unob- 
scured  by  the  color  of  the  overlying  corpuscular  substance. 
Thayer^  has  happily  compared  this  difference  in  refraction  and 
distinctness  of  outline  between  the  tertian  and  quartan  parasites  to 
the  difference  between  a  pale  hyaline  and  a  waxy  cast  in  the 
urine — a  comparison  which  precisely  expresses  these  points  of 
dissimilaritv. 

The  pigment  granules,  fine,  yellowish-brown,  and  violently 
motile  in  the  tertian  variety,  are  coarse,  dark  brown  or  almost 
black,  and  sluggishly  motile,  in  the  quartan  form.  They  early 
tend  to  form  little  spicula  and  rods,  intensely  dark  in  color,  and 
compactly  arranged,  being  frequently  grouped  together  in  masses 
like  coffee  grounds,  in  one  corner  of  the  parasite. 

By  the  time  the  organism  reaches  about  one-half  or  two-thirds 
the  size  of  the  corpuscle  in  which  it  is  contained,  it  may  be  ob- 
served that  its  ameboid  movements,  which  in  the  earlier  stages  of 

1"  Lectures  on  the  Malarial  Fevers."     N.  Y.,  1897. 


MALARIAL    FEVER.  369 

its  existence  were  quite  active,  have  now  become  sluggish,  slow, 
and  inconspicuous.  In  consequence  of  this  limited  motility,  the 
long  tentacular  shoots  of  protoplasm,  so  familiar  in  the  tertian 
form,  are  not  seen,  the  quartan  parasite  inclining  to  form  resting 
figures,  oval,  or  round,  or  somewhat  elongated  in  outline.  The 
pigment  does  not  oscillate  violently,  but  moves -about  a  more 
limited  area,  with  a  sort  of  deliberate,  tugging  motion.  It  is  dis- 
tributed about  the  periphery,  which  it  parallels  for  only  a  short 
distance,  not  tending  to  produce  the  wreathed  designs  commonly 
observed  in  the  tertian  organism  at  a  corresponding  stage  of  its 
maturity. 

As  the  parasite  matures,  its  ameboid  powers  progressively  di- 
minish, until  at  a  period  usually  after  the  forty-eighth  hour  fol- 
lowing the  last  paroxysm  little  or  no  motility  of  either  proto- 
plasm or  of  pigment  is  distinguishable. 

The  corpuscular  host  meanwhile  undergoes  striking  changes 
in  comparison  to  the  erythrocyte  invaded  by  the  tertian  organ- 
ism. Instead  of  becoming  swollen  and  pale,  as  in  the  latter  in- 
stance, on  the  contrary,  it  becomes  shrunken,  darker  colored,  and 
sometimes  "brassy."  It  is  not  until  segmentation  is  imminent, 
or  from  about  ten  to  twelve  hours  before  the  impending  paroxysm, 
that  decolorization  of  the  blood  corpuscle  becomes  marked.  At 
this  period  of  its  cycle,  the  parasite  measures  about  7  or  8  /i  in 
diameter,  and  is  apparently,  although  not  actually,  unconfined  by 
a  corpuscular  envelope,  the  latter  now  having  become  rapidly 
decolorized  and  finally  quite  invisible. 

As  segmentation  approaches,  the  pigment  collects  in  the  center 
of  the  organism,  which  now  becomes  more  opaque  and  de- 
velops a  number  of  refractive  dots,  which  later  become  the  nuclei 
of  from  six  to  twelve  segments,  developed  by  a  progressive  deep- 
ening of  parallel  radial  striations  extending  from  the  periphery  to 
the  center  of  the  parasite.  The  segmenting  quartan  parasite  forms 
a  perfect  rosette,  the  individual  spores  being  of  equal  size  and  of 
the  same  shape,  and  the  collected  mass  of  spores  being  very 
symmetrically  arranged.  Coincidentally  with  segmentation,  a  new 
group  of  young  hyaline  parasites  may  be  found  in  the  hitherto- 
uninvaded  red  corpuscles,  indicating  the  beginning  of  another 
cycle  of  the  parasite's  development,  which,  if  unchecked,  persists 
for  seventy-two  hours. 

Thayer '  mentions  a  star-like  arrangement  of  the  pigment  in 
the  early  stages  of  the  segmenting  quartan  organism,  as  if  the 
granules  had  flowed  inward  in  distinct  streams  during  the  process 
of  collection,  and  this  picture  he  is  inclined  to  consider  character- 

^  Loc.  cit. 
24 


370  GENERAL    HEMATOLOGY. 

istic.  The  author  is  able  to  verify  Thayer's  obser\'ation,  having, 
in  a  limited  experience  with  the  quartan  parasite,  never  failed  to 
find  this  peculiarity,  its  absence  having  been  equally  conspicuous 
in  malarial  organisms  of  other  types. 

The  quartan  parasite  completes  every  phase  of  its  development 
in  the  circulating  blood,  so  that  all  stages  of  its  cycle,  from  the 
earhest  hyaline  forms  to  the  segmenting  and  flagellate  bodies,  may 
be  studied  in  the  peripheral  blood. 

Extyaccllular  pigmented  forms,  which  have  parted  with  all  traces 
of  their  corpuscular  capsule  without  having  undergone  segmenta- 
tion, may  also  be  observed.  They  average  less  in  diameter  than 
similar  forms  of  the  tertian  parasite,  the  largest  of  the  quartan 
forms  being  about  equal  in  size  to  the  smallest  of  the  tertian. 
Their  pigment  granules  are  coarse,  ver}'  dark  colored,  and  situ- 
ated chiefly  toward  the  peripher)^  with  a  greater  or  less  drifting 
inward  of  individual  pigment  clumps  apparently  composed  of  two 
or  three  agglutinated  coarse  granules. 

Flagellate  bodies^  smaller  in  size  and  containing  coarser  granules 
than  corresponding  tertian  forms,  develop  from  these  swollen  ex- 
tracellular parasites,  the  onset  of  flagellation  being  portended  by 
increased  activity  and  centralization  of  the  pigment  in  direct  antici- 
pation of  the  appearance  of  the  flagellate  appendages. 

Degenerate  forms  of  the  parasite,  vacuoHzed,  fragmented,  and 
otherwise  deformed,  may  be  also  obsen^ed,  but  with  less  frequency 
than  in  tertian  fever,  probably  for  the  reason  that  extracellular 
forms  of  the  quartan  parasite  are  not  so  common  as  those  of  the 
tertian  organism.  The  writer  has  especially  noticed  the  infre- 
quency  of  fragmentation  and  other  deformity  of  those  organisms 
which  have  prematurely  emerged  from  their  corpuscular  host, 
atypical  varieties  of  the  more  mature  free  bodies  being  compara- 
tively much  commoner. 

3.  The  Parasite  of  Estivo-atittimjial  Fever.  (Plate  VIII.)  The 
developmental  cycle  of  the  estivo-autumnal  parasite  exhibits 
marked  irregularity  as  to  the  length  of  time  required  for  its  com- 
pletion, in  contrast  to  the  routine  fort>^-eight-  and  seventy-two- 
hour  cycles  in  which  the  tertian  and  quartan  organisms  round  out 
their  life  histories.  In  some  instances  the  cycle  of  the  estivo- 
autumnal  parasite  is  of  only  twent}'-four  hours'  duration,  while  in 
others  it  is  quite  forty-eight  hours,  or  perhaps  longer.  This  in- 
constancy of  type  is  thought  to  depend  upon  some  peculiarity  of 
the  organism,  by  virtue  of  which  the  time  required  for  its  matu- 
ration may  widely  fluctuate  under  different  conditions  of  quite 
obscure  character.  It  is  not  generally  believed  that  the  com- 
mon types  of  fever,  quotidian  and  tertian,  respectively,   depend 


PLATE  Vlll. 


•••#0d^ 


€ 


^  ♦ 


10  11 


>  O 


12  .     13 


14 


% 


t 


5 


19  20  21  22 


15 


16 


17 


18 


-^1 « 


23 


24        ^ 


^ 


26 


25 


Thk  Estivo-Autumnai-  Parasite. 


1.  Normal  erythrocyte. 

2,  3.    Voi/ti,^  hvaliue  rin^- forms. 

4.  5,  6.   Iniracellular  hyaline  forms.     In  4  the  parasite  appears  as  an  irregularly  shaped  disc 
with  a  thinned-oui  central  area.     In  s  and  6  its  ameboid  properties  are  obvious. 

7.  Young  pigmented  intracellular  form.     Note  the  extreme  delicacy  and  small  number  of 

the  pigment  granules.     (Compare  with  6,  Plate  \'I,  and  with  3,  Plate  VII.) 

8.  9.    Later  developmental  stages  of  7. 
ID,  II,  12.    Segmentins:  forms. 

I"^,  14.    Crescentic  forms  at  early  stacres  of  their  development. 

15,  16,  17,  iS,  19.  Crescentic  forms.    In  15  and  19  a  distinct  "  bib"  of  the  erythrocyte  is  visible. 
Vacuolation  of  a  crescent  is  shown  in  18,  and  polar  arrangement  of  the  pigment  in  17. 

20.  Oval  form. 

21,  22.   Spherical  forms. 

23.  Flagellate  form. 

24.  I'acuolation  and  deformitv  of  a  spherical  form. 

2s.    yacHolated  leucocyte  apparently  enclosing  a  dwarfed  and  shrunken  crescent. 
26.   Remains  of  a  shrunken  spherical  form. 

(E.  F.  V^HKR,  fee.) 


MALARIAL    FEVER.  3/1 

Upon  infection  with  two  special  forms  of  the  estivo-autumnal 
parasite,  although  this  view  is  held  by  some  authors,  notably  by 
Mannaberg,^  and  by  Marchiafava  and  Bignami,^  all  of  whom  rec- 
ognize both  a  quotidian  and  a  tertian  variety  of  the  organism  ; 
the  formei-,  furthermore,  describes  a  pigmented  and  an  unpig- 
mented  form  of  the  quotidian  variety. 

Certain  phases  of  the  young  hyaline  forms  of  the  estivo- 
autumnal  parasite  bear  a  striking  resemblance  to  similar  forms  of 
the  tertian  and  quartan  organisms,  but  other  phases  are,  on  the 
contrary,  just  as  strikingly  dissimilar.  As  a  rule,  the  estivo- 
autumnal  hyaline  body  is  much  smaller  than  those  just  described, 
its  margins  are  more  sharply  defined  from  the  corpuscular  sub- 
stance, and  it  appears  to  possess  a  greater  degree  of  refraction. 
But  these  are  minor  points  of  difference,  the  chief  distinction 
relating  to  the  peculiar  morphological  changes  to  be  observed  in 
these  immature  parasites.  At  one  moment  they  may  appear  as 
pale,  rounded  or  somewhat  oval  bodies,  situated  rather  toward 
the  periphery  of  the  corpuscle  than  in  its  center,  and  usually 
possessing  active  ameboid  movements  which  produce  various 
stellate  and  forked  designs.  On  closer  observation,  certain  other 
striking  changes  may  be  noted  in  these  round  forms.  These 
changes  consist  in  the  formation  of  the  so-called  ring-shaped 
bodies,  due  to  the  development  of  a  more  or  less  marked  bicon- 
cavity  of  the  hitherto  flattened  hyaline  body,  either  in  its  center, 
in  event  of  which  the  parasite  appears  as  a  true  ring  or  hoop,  or 
more  toward  its  periphery,  in  which  instance  a  figure  resembling 
a  signet-ring  is  produced.  These  figures  remain  visible  for  a 
variable  length  of  time,  the  parasite  meanwhile  being  apparently 
in  a  resting  stage,  but  sooner  or  later  its  ameboid  powers  are 
reasserted,  with  the  result  that  the  biconcavity  abruptly  disappears, 
converting  the  ring-shaped  body  into  its  original  form  of  an 
ameboid,  flattened  disc.  This  successive  alteration  in  shape, 
from  disc  to  ring  to  disc,  regardless  of  the  other  changes  in  shape, 
is  highly  characteristic  of  the  estivo-autumnal  organism,  and  is 
fully  as  valuable  a  diagnostic  sign  as  the  more  striking  pictures  of 
the  maturer  forms,  to  be  considered  later.  The  size  of  the  ring- 
shaped  parasites  varies  from  less  than  2  //  in  diameter,  to  about 
3  fx.  They  are  rarely  situated  in  the  exact  center  of  the  cor- 
puscles, more  commonly  being  found  lying  midway  between  the 
center  and  the  periphery,  or,  indeed,  quite  upon  the  latter. 

As  the   parasite  matures,  pigment,  in  the   form  of  a  few   ex- 
ceedingly fine,  scattered  granules,  begins  to  appear.     The  gran- 

iNothnagel's  Spec.  Path.  u.  Ther.,  Wien.,  1899,  vol.  ii.,  p.  68. 
2New  Sydenham  Soc,  Transl.,  London,  1894,  vol.  cl.,  p.  i. 


3/2  GENERAL    HEMATOLOGY. 

ules  are  very  few  in  number,  dark  brown  in  color,  and  are  usually 
situated  toward  the  edge  of  the  organism.  They  may  or  may 
not  be  motile,  usually  not.  Strikingly  pigmented  forms  of  the 
estivo-autumnal  parasite  are  never  observed,  in  marked  contrast 
to  the  abundant  fine  pigment  of  the  tertian  forms,  and  to  the  coarse 
granules  typical  of  the  quartan  varieties. 

The  development  of  the  parasite  up  to  this  stage  can  be  studied 
in  the  peripheral  blood,  but  the  older  forms  of  the  pigmented 
bodies,  and  their  final  division  into  spores,  by  segmentation,  occur 
almost  exclusively  in  the  deeper  circulation,  and  must  be  fol- 
lowed out  in  blood  obtained  from  one  of  the  internal  organs,  such 
as  the  spleen,  which  may  be  aspirated  for  this  purpose,  although 
the  procedure  is  not  without  risk  to  the  patient.  In  the  finger 
blood  the  wTiter  has  never  seen  presegmenting  forms  more  ma- 
ture than  those  represented  by  the  young  slightly  pigmented 
parasite,  and  has  never  had  the  good  fortune  to  meet  with  seg- 
menting bodies  except  in  specimens  derived  from  the  spleen. 
The  general  rule  is  to  find  in  the  peripheral  blood  nothing 
more  than  hyaline  ameboid  and  ring-shaped  bodies,  or,  perhaps, 
a  few  organisms  containing  two  or  three  minute  granules  of 
pigment. 

If  now  a  drop  of  blood,  aspirated  from  the  spleen,  is  examined, 
the  remainder  of  the  parasite's  cycle  may  be  traced  with  fair  ac- 
curacy. As  it  approaches  the  stage  of  segmentation^  the  para- 
site develops  into  a  spherical  body,  measuring  from  about  2  to 
6  //  in  diameter,  and  having  a  distinct  outline  which  limits 
it  from  the  surrounding  substance  of  the  red  blood  corpuscle, 
which  it  only  partly  fills.  The  pigment  granules,  which  by 
this  time  are  moderately  but  never  strikingly  increased  in  num- 
ber, show  a  marked  tendency  to  become  concentrated  near  the 
center  of  the  organism.  They  here  exist  as  a  tightly  clumped, 
compact  mass,  in  which  the  identity  of  the  individual  granules 
is  completely  lost,  as  they  have  now  become  fused  into  a  single 
distinct,  dark-colored,  round  or  somewhat  elongated  mass. 

As  segmentation  commences,  the  parasite  becomes  opaque, 
minute  refractive  areas  paralleling  the  periphery  develop,  and 
radial  shadings,  which  later  divide  the  body  usually  into  from 
eighteen  to  twenty  spores,  become  apparent.  The  segmenting 
body  is  smaller  than  that  of  the  tertian  and  quartan  parasites,  but 
it  usually  resembles  the  former  as  to  the  arrangement  and  num- 
ber of  the  individual  segments. 

A  marked  characteristic  of  the  estivo-autumnal  infections  is 
the  early  occurrence  of  degenerative  changes  in  the  invaded 
erythrocytes.     These    changes,   the    '^erythropyknosis"    of  the 


MALARIAL    FEVER.  3/3 

Italian  school,  consist  in  the  development  of  a  pronounced 
''brassy"  appearance  of  the  blood  cell,  together  in  many  in- 
stances with  distinct  crenation  along  its  periphery  and  in  various 
portions  of  its  flat  surface.  Occasionally,  there  appears  to  be  a 
distinct  concentration  of  the  hemoglobin  about  the  parasite,  leav- 
ing portions  of  the  corpuscle  quite  colorless.  This  corpuscular 
degeneration  occurs  early,  even  in  those  cells  occupied  by  the 
youngest  hyaline  bodies,  and  grows  more  and  more  marked,  as 
a  rule,  as  the  parasite  matures.  Simple  decolorization  of  the 
erythrocyte  appears  to  follow  no  fixed  rule,  for  segmenting 
bodies  have  been  observed  in  both  perfectly  hyaline  and  in  ap- 
parently unchanged  corpuscles.  In  Thayer's  experience  the  rim 
of  the  blood  cell  surrounding  the  parasite  has  usually  been 
entirely  devoid  of  color. 

After  the  infection  has  existed  for  a  week  or  more,  examination 
of  the  peripheral  blood,  which  until  now  has  contained  perhaps 
only  ring-shaped  organisms,  reveals  the  presence  of  other  highly 
characteristic  forms  of  the  estivo-autumnal  parasite,  the  round, 
ovoid,  and  crescentic  bodies,  all  belonging  to  the  crescent  group. 
These  forms,  which  are  never  present  in  the  circulation  during 
the  first  days  of  the  fever,  are  prone  to  persist  in  the  blood  for  a 
long  period  after  the  disappearance  of  the  earlier  forms  of  the 
parasite,  and  even  after  all  the  clinical  manifestations  of  the 
attack  have  vanished.  Unlike  other  forms  of  the  malarial  para- 
site, those  of  the  crescent  group  are  peculiarly  resistant  to  the 
effects  of  the  administration  of  quinine,  large  doses  of  this  drug 
having  in  many  instances  no  appreciable  effect  in  causing  their 
disappearance  from  the  peripheral  circulation. 

Crescents  are  now  generally  regarded  as  of  intracellular  origin, 
being  transformed  stages  of  the  full-grown,  pigmented,  intracel- 
lular spherical  bodies  which  have  not  been  involved  in  the  proc- 
ess of  segmentation.  These  non-segmenting  forms  continue 
their  development  within  the  corpuscle,  from  which  they  derive 
more  and  more  pigment,  thus  causing  progressive  decolorization 
of  their  host,  until  finally  all  that  remains  of  the  corpuscle  is  a 
thin  shell  surrounding  the  crescent.  As  their  growth  progresses, 
the  parasite  first  loses  its  regular  spherical  contour,  then  becomes 
drawn  out  into  a  long,  narrow,  spindle-shaped  body,  which  finally 
becomes  bent  in  the  shape  of  a  crescent,  the  convexity  of  which 
lies  next  to,  and  for  some  distance  parallels,  one  margin  of  the 
now  almost  colorless  erythrocyte. 

Owing  to  the  fact  that  the  early  development  of  these  crescentic 
forms  occurs  almost  exclusively  in  the  deeper  circulation,  only  the 
later  phases  of  their  evolution  are  ordinarily  observed  in  the  periph- 


374  GENERAL    HEMATOLOGY. 

eral  blood.  In  fresh  blood  they  appear  as  highly  refractive  cres- 
cent-shaped bodies,  measuring  about  6  or  8  ii  from  pole  to  pole, 
and  possessing  a  distinct  double  outline,  as  if  they  consisted  of 
a  central  darker  body  enclosed  in  a  lighter  colored  membra- 
nous envelope.  Adhering  to  the  concave  surface  of  the  crescent 
a  more  or  less  distinct  *'bib,"  the  remnant  of  the  corpuscular  host, 
may  usually  be  observ^ed.  It  varies  in  color  from  pale  yellow  to 
an  almost  indistinguishable  shade  of  light  lemon,  yet  always,  on 
close  observation,  retaining  sufficient  of  the  corpuscular  color  to 
distinguish  it  from  the  parasite  to  which  it  is  attached.  The 
**bib"  completely  bounds  the  concavity  of  the  crescent  in  some 
instances,  extending  from  pole  to  pole ;  in  other  instances,  and 
this  is  of  commoner  occurrence,  it  is  of  smaller  size,  extending 
only  over  the  central  portion  of  the  concavity.  Occasionally 
crescentic  bodies  totally  devoid  of  all  traces  of  their  corpuscular 
host  are  found,  but  these  forms  are  rare.  The  pigment  is  usually 
arranged  in  a  moderately  compact  clump  in  the  center  of  the 
crescent ;  less  commonly  the  granules  are  scattered  along  the 
long  axis  ;  and  very  rarely  a  distinct  polar  grouping  of  the  pig- 
ment at  both  ends  of  the  crescent  is  seen.  The  pigment  gran- 
ules may  or  may  not  show  active  motility. 

The  ovoid  bodies,  which  are  regarded  simply  as  transitional 
forms  of  the  crescents,  are  of  symmetrically  oval  shape,  and  show 
the  same  refractive  protoplasm  and  apparently  double  outline  ob- 
served in  the  latter.  The  pigment,  which  is  generally  motionless, 
is  arranged  in  an  elongated  clump  in  the  center  of  the  ovoid,  and 
a  partly  decolorized  bib-like  corpuscular  attachment  apparently 
clings  to  one  side  of  the  body.  The  long  diameter  of  the  ovoid 
body  measures  approximately  5  or  6  //  and  its  short  axis  is  about 
2  or  3  /J  across. 

The  round  forms,  derived  from  the  crescentic  and  ovoid  bodies, 
are  the  direct  antecedents  of  the  flagellate  organisms.  They 
appear  as  perfect  spheres,  4  or  5  tj.  in  diameter,  either  attached 
to  a  more  or  less  yellowish  remnant  of  the  erythrocyte,  or  lying 
entirely  free.  Their  pigment  is  prone  to  form  a  central  wreathed 
or  ringed  design. 

The  approach  of  flagellation  is  preceded  by  unusual  activity  of 
the  central  pigment  mass,  coincidentally  with  which  indications 
of  motility  about  the  peripheiy  of  the  parasite  become  apparent. 
The  flagella,  which  are  finally  seen  to  reach  out  from  different 
points  on  the  periphery  of  the  body,  are  similar  in  appearance  to 
those  of  the  tertian  and  quartan  organisms.  Their  size,  however, 
is  about  midway  between  that  of  the  tertian  and  quartan  forms. 

Degenerative  changes  of  the  crescentic,  ovoid,  and  round  bodies 


MALARIAL   FEVER.  3/5 

occur,  being  evidenced  by  the  development  of  vacuolization,  and 
occasionally  by  apparent  fragmentation. 

Pigmented  leucocytes  are  found  in  the  blood 

Pigmented      of  all  types  of  malarial  infection,  and  this  fact 
Leucocytes  AND  alone,  irrespective  of  the  presence  of  the  parasites 
Phagocytosis,   themselves,  is  an  extremely  valuable  diagnostic 
clue  to  the  condition. 

In  tertian  and  quartan  infections  the  large  mononuclear  and 
polymorphonuclear  leucocytes  are  the  pigment-bearing  cells,  the 
granules  being  found  either  scattered  in  fine  masses  or  in  fused 
angular  blocks  throughout  the  body  of  the  leucocyte.  Although 
both  of  these  forms  of  leucocytes  show  this  evidence  of  having 
acted  the  role  of  phagocytes,  actual  visual  proof  of  the  performance 
of  this  function  by  the  mononuclear  forms  is  wanting.  The  phe- 
nomenon of  phagocytosis  by  the  polymorphonuclear  leucocytes 
may,  however,  be  watched  in  the  fresh  specimen,  and  these  cells 
may  be  seen  to  engulf  bits  of  free  pigment,  flagellate  bodies,  bas- 
tard forms  of  extracellular  parasites,  and  even,  rarely,  true  seg- 
menting bodies.  Distinct  periodicity  characterizes  the  perform- 
ance of  phagocytosis  in  tertian  and  quartan  infections,  this  process 
being  most  conspicuous  at  the  time  of  segmentation,  during  and 
shortly  after  the  paroxysm,  when  the  extracellular  forms  of  the 
organism  are  present  in  the  blood  in  greatest  number.  Phagocy- 
tosis is  sometimes  seen  during  the  interparoxysmal  interval,  when 
only  the  extracellular  forms  of  parasites  which  have  prematurely 
escaped  from  their  corpuscular  host  are  attacked. 

In  estivo-autumnal  infections  macrophages,  derived  from  the 
spleen,  bone  marrow,  liver,  and  blood  vessel  endothelium,  act  as 
phagocytes,  as  well  as  the  mononuclear  and  polymorphonuclear 
cells  which  alone  exercise  this  function  in  the  regularly  intermit- 
tent fevers.  Phagocytosis  is  much  less  periodical  than  in  tertian 
and  quartan  infections,  for  while  it  is  true  that  pigmented  leuco- 
cytes are  most  numerous  in  the  blood  at  the  time  of  segmenta- 
tion, it  is  also  true  that  they  may  also  be  observed  in  great  num- 
bers during  the  interval — a  fact  which  is  explained  chiefly  by  the 
practically  continuous  segmentation  which  goes  on  in  these  infec- 
tions, because  of  the  presence  in  the  blood  of  multiple  groups  of 
the  parasite.  Phagocytosis  in  estivo-autumnal  fever  differs  from 
that  of  tertian  and  quartan  infections  in  that  in  the  former  inclu- 
sion of  both  parasite  and  corpuscular  host  may  occasionally  be  ob- 
served— a  phenomenon  which  does  not  occur  in  the  latter.  Thus, 
in  addition  to  free  pigment,  and  extracellular,  segmenting,  and  flag- 
ellate forms,  the  phagocytic  leucocytes  are  found  also  to  contain 
whole  or  portions  of  necrobiotic  erythrocytes,  some  of  the  latter, 


376 


GENERAL    HEMATOLOGY. 


perhaps,  enclosing  parasites.  Osier  ^  has  observed  the  phagocy- 
tosis of  crescentic  forms,  and  the  writer  believes  he  has  observed 
the  result  of  this  phenomenon  in  a  single  instance.  (See  Plate 
VIII.,  figure  25.) 

Differential  Table  of  the  Malarial  Parasites' 


Tertian  Parasite. 


Quartan  Parasite. 


Cycle,  48  Hours. 


Cycle,  72  Hours. 


Hyaline  body  larger  than 
that  of  quartan  and  estivo- 
autumnal  organisms  ;  out- 
line indistinct ;  ameboid 
movements  exceedingly 
active  ;  long  pseudopodia 
common. 


Pigment  granules  fine^  very 
active,  and  of  yellowish 
brown  color  ;  more  or  less 
peripherally  arranged. 


Mature  parasite  about  7  //  in 
diameter. 

Segmenting  bodies  consist 
of  from  15  to  30  segments,  j 
arranged  in  an  irregular 
racemose  figure  about  one 
or  more  central  pigment 
clumps. 


Preflagellate  forms  consist 
of  swollen,  spherical  pig- 
mented bodies  as  large  as 
10-12  fi  in  diameter. 


Flagellate  form  larger  than 
that  of  quartan  and  estivo- 
autumnal  parasite. 

Erj-throcyte  becomes  very 
pale  and  swollen. 


Hyaline  body  smaller  than 
that  of  tertian,  but  usu- 
ally larger  than  that  of 
estivo-autumnal  organ- 
ism ;  outline  distinct ; 
ameboid  movements 
slow,  except  in  early 
forms  ;  marked  pseudo- 
podial  branching  un- 
common. 

Pigment  granules  coarse, 
sluggish,  and  of  dark- 
brown  color  ;  peripheral 
arrangement  striking. 


Matiu-e  parasite  about  5  u 
in  diameter. 

Segmenting  bodies  consist 
of  from  6  to  1 2  segments, 
arranged  in  regular  ro- 
sette form  about  a  single, 
compact,  central  pigment 
mass,  the  latter  often  be- 
ing radially  grouped  in 
the  early  stages  of  spor- 
ulation. 

Preflagellate  forms  consist 
of  swollen,  spherical 
pigmented  bodies  as  large 
as  6-8  /z  in  diameter. 


Flagellate  form  smaller 
than  that  of  tertian  and 
estivo-autumnal  parasite. 

Erythrocyte  becomes  dark 
and  contracted. 


ESTIVO-AUTUMNAL  PaRASITE 


Cycle,  24  to  48  Hours 
or  Longer. 


Hyaline  body  smaller  than 
that  of  tertian  and  quar- 
tan organisms ;  outline 
ver}'  sharp  and  distinct ; 
ameboid  movements  ac- 
tive in  early  stages ; 
ring-  and  disc-shaped 
forms. 


Pigment  granules  exceed- 
ingly fine  and  scanty  ; 
may  be  either  motion- 
less or  motile  ;  periph- 
eral arrangement  often 
marked. 

Mature  parasite  from  1. 5 
to  7  //  in  diameter. 

Segmenting  bodies  consist 
of  from  18  to  20  or  more 
segments,  arranged 
either  as  a  regular  ro- 
sette or  irregularly  about 
a  single  compactly  fused 
central  pigment  clump. 


Preflagellate  forms  consist 
of  spherical  pigmented 
bodies,  5-6//  in  diam- 
eter, and  derived  from 
crescentic  and  ovoid 
forms  with  which  they 
are  associated. 

Flagellate  form  smaller 
than  that  of  tertian,  but 
larger  than  that  of  quar- 
tan parasite. 

Erythrocyte  becomes 
brassy  and  crenated. 


TccJmiqiie  of  the  Blood  Examination.      For  diagnostic  purposes' 
the  fresh,  unstained  blood  film  should  be  invariably  preferred  to 
the  dried,  stained  specimen,  for  in  the  latter  not  only  are  the  ame- 

^  British  Med.  Joum.,  1887,  vol.  i.,  p.  556. 


MALARIAL   FEVER.  377 

boid  movements  of  the  parasite  and  the  dancing  of  the  pigment 
necessarily  lost,  but  much  of  the  morphology  and  the  finer  struc- 
ture of  the  organism  is  also  greatly  altered.  The  blood  is 
obtained  in  the  usual  manner,  and  a  drop  used  which  is  small 
enough  to  insure  an  exceedingly  thin  film,  consisting  of  a  single 
layer  of  corpuscles,  each  lying  edge  to  edge,  so  that  every  portion 
of  their  flat  surfaces  may  be  readily  searched  for  foreign  bodies. 
Specimens  in  which  most  of  the  cells  stand  on  edge,  piled 
together  in  heaps  and  rouleaux,  are  entirely  unsuitable,  if  intra- 
cellular forms  of  the  parasite  are  being  searched  for,  since  in  such 
films  only  the  extracellular  forms  are  visible.  Thin,  even  films 
are  facilitated  by  gently  heating  the  slide  over  an  alcohol  flame,  or 
by  instructing  an  assistant  to  rub  the  surface  of  the  slide  vigorously 
with  a  dry  towel  before  making  the  spread.  If  the  examination  is 
likely  to  be  prolonged,  it  is  advisable  to  ring  the  cover-glass  with 
cedar  oil  or  with  vaseline,  to  prevent  crenation  of  the  corpuscles. 

Dried  blood  films,  prepared  in  the  usual  way,  may  be  used  in 
case  the  specimens  must  be  sent  some  distance  for  examination. 
Such  specimens  may  be  stained  with  various  aniline  dyes,  as 
already  directed.  Polychrome  methylene-blue  gives  the  sharpest 
differentiation  of  the  parasite's  histological  structure,  but  solutions 
of  thionin  and  of  eosin  and  methylene-blue  also  will  prove  useful. 
(See  pages  67  and  69.) 

No  magnification  can  be  too  great  in  studying  the  finer  points  of 
the  malarial  parasite,  so  that  a  -^^  inch  oil-immersion  objective, 
with  at  least  a  1^  inch  ocular,  should  be  habitually  employed 
for  the  microscopical  examination.  While  it  is  frequently  con- 
venient to  search  for  individual  parasites  with  a  -g-  or  a  ^  inch 
lens,  one  cannot  well  dispense  with  an  immersion  objective  in 
distinguishing  their  finer  characteristics.  The  substage  condenser 
and  iris  diaphragm  should  be  so  adjusted  that  the  field  is  dimly 
illuminated,  and  not  drowned  in  a  flood  of  white  light.  When  the 
ameboid  movements  of  the  parasite  are  to  be  studied  at  length,  a 
warm  stage  is  useful,  but  not  essential,  if  the  temperature  of  the 
room  is  not  too  low. 

The  best  time  for  the  examination  is  a  few  hours  before  the 
onset  of  the  expected  paroxysm,  at  which  period  it  is  common  to 
find  full-grown  pigmented  organisms,  and  often  an  occasional 
segmenting  form,  if  the  specimen  is  from  a  tertian  or  quartan  in- 
fection. In  estivo-autumnal  fever  relatively  large  ring-  and  disc- 
shaped bodies,  containing  exceedingly  delicate  pigment  granules, 
are  usually  abundant  at  this  time.  Hyaline  intracellular  forms 
are  most  numerous  in  the  blood  a  few  hours  subsequent  to  the 
paroxysm,  in  all  three  forms  of  the  infection. 


3/8  GENERAL    HEMATOLOGY. 

The  writer  would  urge  the  beginner  systematically  to  study  the 
development  of  a  group  of  parasites  by  examining  the  blood  of  a 
single  case  of  malarial  fever  at  frequent  intervals  between  the 
paroxysms.  For  example,  the  life  history  of  the  tertian  parasite, 
from  the  youngest  hyaline  form  to  the  segmenter  and  the  flagel- 
late body,  may  be  traced  in  most  cases  of  tertian  fever,  if  the 
blood  is  examined  ever>^  three  or  four  hours,  day  and  night,  for  a 
period  of  forty-eight  hours.  Such  a  collated  series  of  observa- 
tions, although  they  entail  close  and  tiresome  application  for  the 
time,  will  prove  more  profitable  to  the  student  in  his  comprehen- 
sion of  the  organism's  developmental  cycle  than  dozens  of  hap- 
hazard examinations  made  in  many  different  cases  at  odd  times. 

To  the  unpractised  eye  a  number  of  artefacts  occurring  in  fresh 
blood  specimens  may  for  a  time  be  confused  with  the  malarial  par- 
asite, but  careful  observation  linked  to  an  increased  familiarity 
with  the  appearance  of  the  organism  and  of  its  counterfeits,  will 
eliminate  such  sources  of  error.  The  following  are  the  principal 
objects  which  require  to  be  differentiated  from  the  malarial  par- 
asite :  (i)  The  central  biconcavity  of  the  normal  erythrocytes; 
(2)  morphological  changes  in  the  erythrocytes,  and  (3)  hemoconiae. 

1.  At  first  glance,  the  pale  central  biconcavity  of  the  erythro- 
cyte somewhat  resembles  the  young  hyahne  tertian  parasite,  for 
both  have  an  indistinct  outline  which  merges  with  the  surround- 
ing corpuscular  substance.  But  the  parasite  is  rarely  in  the  cen- 
ter of  the  blood  cell,  it  is  actively  ameboid,  and  it  possesses  a 
characteristic  pearly-gray  appearance.  On  the  other  hand,  the 
pale  area  of  the  corpuscle  is  in  the  center  of  the  normally  shaped 
blood  cell,  it  never  exhibits  ameboid  powers,  and  its  appearance 
is  clean  white  or  yellowish-white.  It  is,  of  course,  uncolored  in 
the  stained  specimen. 

2.  The  morphological  changes  in  the  erythrocyte,  which  may 
be  mistaken  for  malarial  organisms,  are  those  produced  by  vac- 
uolization, crenation,  and  fragjnentation  of  these  cells.  Vacuoles 
appear  as  highly  refractive,  clean-cut,  spherical  bodies  which 
possess  more  or  less  oscillating,  rotar)^  motility,  in  contrast  to 
the  dimmer,  more  vaguely  outlined,  truly  ameboid  forms  of  the 
hyaline  malarial  parasite.  The  spicula  of  crenated  red  cells  may 
in  a  very  dim  illumination  of  the  object  appear  at  first  glance 
somewhat  like  the  coarse  granules  of  the  mature  pigmented  par- 
asite, but  a  change  of  focus  and  a  wider-open  diaphragm  im- 
mediately dispels  the  illusion.  Fragmentation  of  the  erythro- 
cytes, as  the  result  of  thermic  influences,  may  produce  a  most 
bizarre  and  peculiar  variety  of  designs,  the  most  confusing  of 
which  is  a  sort  of  flagellate  appendage  which  appears  to  originate 


MALARIAL   FEVER.  3/9 

in  a  fragmented  sphere  of  corpuscular  substance,  to  which  it  is 
attached.  The  size  of  this  body,  however,  is  far  too  small  to  be 
mistaken  seriously  for  a  true  malarial  flagellate  body,  for  its 
spherical  portion,  which  is  unpigmented  and  tinged  with  hem- 
oglobin, measures  only  about  2 /i  in  diameter;  while  the  flag- 
ellate appendage,  usually  single,  is  represented  by  a  colorless, 
thin  line  not  often  longer  than  3  or  4  /i,  and  tremulously  motile, 
not  ameboid  like  the  flagellum  of  the  malarial  body.  This 
sort  of  a  flagellate  figure  is  very  commonly  seen  in  blood  slides 
which  have  become  chilled. 

3.  Hemoconice  are  readily  distinguished  by  their  very  small 
size,  spherical  contour,  and  glistening,  fat-like  appearance.  It 
sometimes  happens  that  one  of  these  granules  of  "blood-dust," 
in  its  Brownian  excursion  across  the  field  of  the  microscope,  lies 
over  the  flat  surface  of  an  erythrocyte,  simulating  for  the  mo- 
ment, a  small,  hyaline,  intracellular  parasite.  It  seems  probable, 
also,  that  one  of  these  granules,  observed  just  at  the  instant  it 
crosses  the  rim  of  the  blood  cell,  has  been  mistaken  for  a  hyaline 
spore  in  the  act  of  invading  an  erythrocyte,  by  those  who  be- 
lieve that  they  have  witnessed  this  remarkable  phenomenon. 

Well-marked  anemia,  developing  early  during 
Hemoglobin   the  course  of  the  disease,  and  proportionate  in 
AND  degree  to  the  severity  of  the  attack,  is  a  con- 

Erythrocytes.  spicuous  clinical  sign  in  the  malarial  fevers. 

Dionisi,^  Thayer,^  and  other  authors  have  ob- 
served that  a  loss  of  hemoglobin  and  a  diminution  in  the  number 
of  erythrocytes  occur  after  every  paroxysm,  this  being  due  largely 
to  the  destruction  of  immense  numbers  of  parasite-containing  cor- 
puscles by  the  maturation  of  the  organisms,  and  in  part  to  the 
presence  in  the  blood  of  other  substances  destructive  to  the  un- 
invaded  red  cells.  The  loss  is  especially  marked  after  the  early 
paroxysms,  being  of  slighter  degree  after  those  occurring  later 
in  the  course  of  the  disease.  On  the  other  hand,  during  the 
paroxysm  a  tendency  on  the  part  of  the  red  corpuscles  to  increase 
in  number  has  been  noted. 

The  loss  is  more  moderate  in  the  regularly  intermittent  tertian 
and  quartan  types  of  malaria  than  in  the  estivo-autumnal  form. 
In  the  former  types,  the  regenerative  powers  of  the  blood  are 
usually  prompt  and  vigorous,  so  that  the  normal  number  of  cells 
is  almost  restored  by  the  onset  of  the  succeeding  paroxysm.  It 
is  owing  to  this  fact  that  repeated  paroxysms  must  occur  before 
the  anemia  becomes  striking. 

^  Lo  Sperimentale,  1891,  f.  iii.  and  iv.,  p.  284. 
2  Loc.  cit. 


380  GENERAL    HEMATOLOGY. 

In  the  estivo-autumnal  form  the  loss  is  far  greater,  a  decrease 
of  500,000  or  more  corpuscles  per  cubic  milHmeter  sometimes 
occurring  after  a  single  paroxysm,  such  a  marked  loss  as  this  being 
associated  especially  with  cases  in  which  excessive  numbers  of 
parasites  are  present  in  the  blood.  Even  in  non-febrile  cases  of 
larval  malarial  fever,  Marchiafava  and  Bignami  ^  have  observed 
more  or  less  anemia.  Organisms  of  the  crescent  group  appear 
to  exert  no  influence  in  causing  diminution  in  the  number  of 
erythrocytes.  Regeneration  of  the  blood  is  slow  in  the  estivo- 
autumnal  fever,  so  that  the  loss  of  hemoglobin  and  of  corpuscles 
is  not  made  up  during  an  inter-paroxysmal  interval,  in  consequence 
of  which  more  marked  and  graver  anemias  are  commoner  than 
in  the  tertian  and  quartan  fevers.  If  the  anemia  is  markedly 
developed  during  the  early  stages  of  the  infection,  the  corpus- 
cular decrease  is  aggravated  slightly,  if  at  all,  by  the  following 
paroxysms. 

In  malarial  hemoglobinuria  an  enormous  destruction  of  cor- 
puscles occurs,  "  a  destruction,"  in  the  words  of  Thayer,^  *'  too 
great,  probably,  to  be  dependent  wholly  on  the  disintegration  of 
parasitiferous  elements.  We  are  compelled  ...  to  suppose 
the  existence  of  some  condition  which  renders  the  ujiinfected  red 
blood  corpuscles  unusually  vulnerable,  possibly  some  change  in 
the  blood  serum  by  which  its  isotonicity  is  markedly  disturbed." 

Usually  the  hemoglobin  loss  is  relatively  greater  than  the  cor- 
puscular decrease,  moderately  low  color  indices  being  the  general 
rule,  but  in  some  cases  both  are  parallel.  In  estimates  made 
by  the  author  in  tAventy-two  cases  of  malarial  fever,  nearly  all 
of  the  tertian  type,  the  hemoglobin  averaged  60.8  per  cent,  of 
normal,  ranging,  in  the  individual  case,  from  30  to  80  per  cent. 
The  color  index  in  these  cases  averaged  0.87,  the  extremes  being 
0.55  and  1. 51. 

The  variations  in  hemoglobin  were  as  follows  : 

Between  80-90  per  cent,  in  3  cases. 


'*       70-80 

''  6 

**        60-70 

"  5 

*'      50-60 

''  2 

''      40-50 

"  4 

30-40 

"   2 

Average : 

60.8 

per  cent. 

Highest : 

80.0 

t( 

Lowest : 

30.0 

(( 

^  Loc.  cit. 

2Loc.  cit. 

MALARIAL   FEVER.  3^1 

The  loss  of  corpuscles  varies  within  wide  Hmits,  being  most 
marked  in  severe  and  in  long-standing  cases.  Counts  as  low  as 
500,000  per  cubic  millimeter  have  been  reported/  and  the  num- 
ber falls  to  from  1,000,000  to  2,000,000  in  a  considerable  pro- 
portion of  cases.  In  the  above  series,  the  average  of  the  twenty- 
two  counts  showed  3,481,818  eiythrocytes  per  cubic  millimeter, 
individual  cases  varying  from  1,410,000  to  4,880,000.  The  range 
of  the  counts  is  shown  thus,  in  tabular  arrangement : 

Between  4,000,000-5,000,000  in  11  cases. 
<*       3,000,000-4,000,000  ^'    2     *' 
"        2,000,000-3,000,000  '^    6     ** 
**        1,000,000-2,000,000  "     3     *' 


Average  : 

3,481,818  per  cb.  mm. 

Highest : 

4,880,000    "        '' 

Lowest : 

1,410,000    ''        ^' 

In  seven  cases  cHnically  designated  as  '' malarial  cachexia,"  in 
which  parasites  were  not  found  in  the  circulating  blood,  the  fol- 
lowing results  were  obtained  :  hemoglobin  ranged  from  40  to  52 
per  cent.,  the  average  being  45.5;  color  index,  from  .41  to  1.13, 
averaging  .66;  and  erythrocytes,  from  2,300,000  to  4,861,000 
per  cubic  millimeter,  with  an  average  of  3,406,250. 

As  regeneration  of  the  blood,  which  is  generally  slow,  takes 
place,  the  normal  percentage  of  hemoglobin  is  reached  more 
slowly  than  that  of  the  corpuscles— in  fact,  in  some  instances  of 
post-malarial  anemia  subnormal  hemoglobin  percentages  persist 
for  indefinite  periods  after  convalescence  has  been  established. 

Histological  changes  in  the  erythrocytes  are  marked  in  relation 
to  the  severity  of  the  anemia.  Pallor  of  the  corpuscles  is  often 
conspicuous,  and  poikilocytosis  and  deformities  of  size  are  pres- 
ent in  severe  cases.  In  such  instances  small  percentages  of  nor- 
moblasts, and  of  atypical  nucleated  forms  are  not  infrequently 
found,  sometimes  in  association  with  an  occasional  megaloblast. 
In  severe  cases  both  polychromatophilia  and  basic  granular  de- 
generation of  the  erythrocytes  are  familiar  findings. 

The  following  four  types  of  post-malarial  anemia  are  distin- 
guished by  Bignami  and  Dionisi.^ 

I.  Anemiae  in  which  examination  of  the  blood  shows  altera- 
tions similar  to  those  observed  in  secondary  anemiae,  from  which 

iKelsch:  Archiv.  de  Physiologic,  1875,  vol.  ii.,  p.  690.      Ibid.,  1876,  vol.  iii., 

^"  tSntralbl.  f.  Allg.    Path.  u.  path.  Anat.,  1894,  vol.  v.,  p.  422.      (Quoted  from 
Thayer  and  Hewetson  :  "The  Malarial  Fevers  of  Baltimore,"  Baltimore,  i895.  P- 

58-) 


382  GENERAL    HEMATOLOGY. 

they  differ  only  in  that  the  leucocytes  are  diminished  in  number. 
The  greater  part  of  these  cases  go  on  to  recovery  ;  a  few,  without 
any  further  change  in  the  hematological  condition,  pursue  a  fatal 
course. 

2.  Anemiae  in  which  the  examination  of  the  blood  shows  altera- 
tions similar  to  those  seen  in  pernicious  anemia — presence  of  gigan- 
toblasts.     These  cases  end  fatally. 

3.  Anemiae  which  are  progressive,  as  a  result  of  the  lack  of 
compensation  by  the  marrow  for  losses  brought  about  by  the 
infection.  At  autopsy  the  marrow  of  the  long  bones  is  found  to 
be  wholly  yellow,  while  the  marrow  of  the  flat  bones  is  also  poor 
in  nucleated  red  corpuscles. 

4.  Chronic  anemiae  of  the  cachectic,  which  differ  from  the  above- 
mentioned  types  by  clinical  and  anatomical  characteristics  in  that 
the  special  symptoms  of  malarial  cachexia  prevail,  while  one  ob- 
serves, post-mortem,  a  sort  of  sclerosis  of  the  bone  marrow.  The 
marrow  of  the  long  bones  is  red  and  of  an  increased  con- 
sistency; the  giant  cells  are  very  numerous  and  many  are  ne- 
crotic; the  nucleated  red  blood  corpuscles  are  very  rare,  and 
the  colorless  polymorphonuclear  corpuscles  are  present  in  small 
numbers. 

Distinct   leucopenia,   or  at    least    an    absence 
Leucocytes,    of  leucocytosis,  is  almost  invariably  found  in  the 
uncomplicated  case  of  malarial  fever,  the  excep- 
tions to  this  general   rule  occurring  during  the  grave  paroxysms 
of  the  pernicious  type  of  fever. 

The  subnormal  range  of  the  leucocytes  in  malarial  fever  was 
early  noted  by  Kelsch,^  and  has  been  repeatedly  confirmed  by 
other  investigators  since  the  former's  statement  of  the  fact. 
Billings,^  in  particular,  has  carefully  studied  this  question,  and 
his  examinations,  100  in  number,  show  that  the  number  of  leu- 
cocytes averaged  4,323  per  cubic  millimeter,  or  a  decrease  of 
about  38  per  cent,  below  normal.  In  71  counts  made  by  this 
reporter  in  16  cases,  in  order  to  determine  the  effects  of  the 
malarial  paroxysms  on  these  cells,  it  was  found  that  during  the 
early  part  of  the  paroxysm  their  number  gradually  increased, 
the  maximum  being  reached,  as  a  rule,  two  or  three  hours  after 
the  chill.  Following  this  maximum  increase  the  number  steadily 
and  progressively  decreased,  hour  by  hour,  until  the  minimum 
was  reached  during  the  period  of  subnormal  temperature,  at  the 
end  of  the  paroxysm.  During  the  afebrile  interval  the  number 
of  leucocytes  is  distinctly  subnormal,  but  it  rises  slightly  again 

1  Loc.  cit. 

2  Johns  Hopkins  Hosp.  Bull.,  1S94,  vol.  v.,  p.  89. 


MALARIAL   FEVER.  383 

just  before  the  onset  of  the  following  chill,  so  that  the  average 
count  is  slightly  higher  immediately  before  the  chill  than  during 
the  rest  of  the  interval. 

In  the  author's  series,  above  referred  to,  the  average  of  i8 
counts  showed  5,211  leucocytes  per  cubic  millimeter,  the  lowest 
count  being  2,000,  and  the  highest  11,600.  All  these  counts 
were  made  during  the  intei-val  between  the  paroxysms,  in  un- 
complicated cases,  so  far  as  it  was  possible  to  determine. 

The  counts  ranged  as  follows  : 


Above 

10, 

000  in 

2 

cases. 

Between  8, 

000- 

-10, 

000 

( < 

3 

(( 

-        6, 

000 

-  8, 

000 

a 

2 

(( 

''        4, 

000 

-  6, 

000 

(( 

6 

ti 

''        2, 

ooo- 

-  4, 

000 

(I 

5 

li 

Average : 

5, 

211 

per 

cb 

.  mm. 

Highest : 

II, 

600 

<< 

(( 

it 

Lowest : 

2, 

000 

<< 

i( 

a 

In  the  7  cases  of  "  malarial  cachexia  "  the  number  of  leuco- 
cytes to  the  cubic  millimeter  ranged  from  4,500  to  44,000,  the 
average  being  16,971.  Five  of  these  cases  had  distinct  leuco- 
cytosis,  a  condition  believed  by  Thayer  to  occur  in  some  of  the 
post-malarial  anemias,  usually  those  following  short-lived  infec- 
tions. 

Relative  lymphocytosis,  sufficiently  decided  to  become  a  striking 
characteristic  of  the  condition,  is  practically  a  constant  qualitative 
change.  As  a  rule,  the  increase  affects  chiefly  the  large  lympho- 
cytes. Stephens,^  in  a  recent  study  of  ''blackwater  fever,"  found 
that  this  type  of  cells  often  constituted  20  per  cent.,  30  per  cent, 
or  even  50  per  cent,  of  the  total  number  of  leucocytes  ;  further- 
more, he  states  that  this  relative  increase  bears  an  inverse  relation 
to  the  temperature  curve,  being  least  marked  during  the  pyrexia, 
and  greatest  during  the  periods  of  apyrexia.  This  feature  persists 
in  some  cases  with  leucocytosis,  as  well  as  in  those  with  leuco- 
penia.  The  percentage  of  eosinopJiiles  is,  as  a  rule,  subnormal, 
and  this  variety  of  cells  is  frequently  absent ;  more  rarely  they 
are  slightly  increased,  especially  in  some  of  the  post-malarial 
anemias.  Myelocytes  in  small  numbers  are  very  commonly 
found,  in  the  writer's  experience,  especially  in  estivo-autumnal 
infections,  and  in  cases  with  pronounced  anemia.  In  9  differential 
counts,  made  in  cases  of  the  series  above  referred  to,  the  relative 
percentages  of  the  different  forms  of  leucocytes  averaged  as 
follows  : 

^  Lancet,  1901,  vol.  i.,  p.  848. 


384  GENERAL    HEMATOLOGY. 

Small  lymphocytes 15-33  P^^  cent 

Large  lymphocytes  and  '^transitional"  forms.  15.94    ''      " 

Polynuclear  neutrophiles 67.00 

Eosinophils 83 

Myelocytes 51 


( e         ( ( 


Practically  the  same  figures  were  obtained  from  the  similar  ex- 
amination of  3  cases  of  anemia  associated  with  malarial  cachectic 
conditions. 

The  d/ood  plaques  are  greatly  decreased  in  number,  as  in  other 
febrile  conditions. 

The  detection  of  the   specific  parasite  in  the 

Diagnosis,  circulating  blood  is  proof  positive  of  malarial 
fever,  the  exact  type  of  which  may  be  determined 
by  close  study  of  the  organism's  peculiarities.  Even  if  nothing 
more  definite  than  pigmented  leucocytes  is  found,  the  evidence 
is  strongly  in  favor  of  some  form  of  paludism.  The  progressive 
anemia,  and  the  leucopenia  involving  a  relative  decrease  in  the 
polynuclear  neutrophiles,  are  also  valuable  side-lights  on  the 
diagnosis.  An  obscure  intermittent  fever  which  shows  leucocy- 
tosis  is  almost  certainly  not  malarious. 

The  chills  and  pyrexia  of  sepsis  and  of  tuberculosis  are  not  in- 
frequently misinterpreted  as  symptoms  of  malarial  fever.  In 
septicemia  leucocytosis  is  usually  found,  but  even  should  the 
leucocytes  not  be  increased  in  number,  they  fail  to  show  the 
relative  lymphocytosis  of  malarial  blood.  In  pure  tuberculosis 
the  blood-picture  of  malaria  may  be  counterfeited,  in  so  far  as  the 
quantitative  and  qualitative  leucocyte  changes  are  concerned,  and 
in  such  instances  the  parasite  must  be  demonstrated  to  settle  the 
diagnosis.  The  same  leucocyte  changes  also  occur  in  entcjic 
fever,  the  differentiation  of  which  has  been  alluded  to  above. 
(See  page  331.)  It  maybe  added  that  in  those  rare  instances  of 
coincident  typhoid  and  malaria  the  blood  of  the  same  individual 
may  contain  parasites  and  give  a  positive  serum  reaction  with  the 
Eberth  bacillus. 

XXXVII.     MALIGNANT  DISEASE. 
Carcinoma. 

There  is  no  deviation  from  normal  in  the  coagu- 

General       lability  and  the  amount  of  fibrin,  except  in  the 

Features,      event    of   ulcerative    and   inflammatory'  changes 

affecting  the  tumor,  but,  should  these  conditions 

be  present,  coagulation  may  occur  with  abnormal  rapidity,  and 

the  density  of  the  fibrin  network  almost  invariably  increases.     The 


MALIGNANT    DISEASE.  385 

Specific  gravity  may  or  may  not  be  subnormal,  according  to  whether 
or  not  the  percentage  of  hemoglobin,  which  it  parallels,  is  reduced. 
The  alkalinity  of  the  blood  is  almost  always  decreased  in  gastric 
cancer,  according  to  Krokiewicz.^ 

Relatively  large  amounts  of  sugar  (as  high  as  3  parts  per 
1,000)  have  been  found  in  the  blood  of  patients  suffering  from 
various  forms  of  carcinoma,  especially  visceral  cancer,  in  contra- 
distinction to  more  superficial  growths,  involving,  for  example,  the 
skin  and  mucous  membranes.  In  no  other  disease  except  diabetes 
has  more  than  one-third  of  the  above-named  quantity  of  sugar  been 
detected  in  the  blood,  according  to  the  analyses  made  by  Trinkler.^ 

Examination  of  the  blood  for  the  detection  of  a  specific  parasite 
of  cancer  has  thus  far  proved  unconvincing,  although  much  care- 
ful work  has  been  done  with  this  purpose  in  view.  Gaylord  ^  has 
recently  described  protozoa  similar  to  the  bodies  previously  dis- 
covered by  RusselP  and  by  Plimmer,^  to  which  he  ascribes 
specific  properties,  claiming  *'  in  all  cases  of  carcinoma  and  sarcoma 
thus  far  examined  in  which  cachexia  was  well  marked,  that  the 
organisms  can  be  detected  in  the  peripheral  blood."  This  an- 
nouncement, while  of  great  interest  and  importance,  must  receive 
corroboration  by  other  investigators  before  it  can  merit  general 
acceptance.  The  careful  studies  of  33  cases  of  cancer,  recently 
completed  by  Maragliano,^  have  apparently  disproved  the  state- 
ments of  a  number  of  authors,  who  claimed  to  have  cultivated 
blastomycetes  from  the  circulating  blood  in  this  disease. 

During  its  incipiency  carcinoma  gives  rise  to 

Hemoglobin     practically  no  changes  in  the  erythrocytes  or  their 

AND  hemoglobin  content,  or  at  the  most  causes  simply 

Erythrocytes,  a  moderate  diminution  in   the  latter.      As  the 

disease    progresses    and    extends,    and    as    the 

cachexia  of  the  patient  becomes  more  pronounced,  a  secondary 

anemia    develops,    attaining   but    a    moderate    degree    in    some 

instances,  but  in  others  becoming  so  extreme  as  to  simulate  in 

some  particulars  true  pernicious  anemia.     Since  the  hemoglobin 

loss  usually  anticipates  the  cellular  decrease,  the  blood-picture  of 

early  cancer  not  infrequently  resembles  that  of  chlorosis.     Later, 

however,  these  conditions   may  be  reversed,  so  that  the  index 

rises.      In  the  author's  experience,  the  average  hemoglobin  loss 

'  Archiv.  f.  Verdauungskrankh.,  1900,  vol.  vi.,  p.  25. 
2Centralbl.  f.  d.  med.  Wissensch.,  1890,  vol.  xxviii.,  p.  498. 
3  Am.  Journ.  of  Med.  Sc,  1901,  vol.  cxxi.,  p.  503. 
♦British  Med.  Journ.,  1900,  vol.  ii.,  p.  1356. 
5  Practitioner,  1899,  vol.   Ixvii.,  p.  430. 

6Gaz.  degli  Osp.  e.  d.  Clin.,  19CX),  vol.  xxi.,  p.  1538.     Also,  Sem.  med.,  1901, 
vol.  xxi.,  p.  63. 

25 


386  GENERAL    HEMATOLOGY. 

has  amounted  to  somewhat  more  than  40  per  cent.,  and  the 
erythrocyte  decrease  to  about  25  per  cent,  of  normal.  The  color 
index  tends  to  range  moderately  low,  usually  from  20  to  30  points 
below  the  standard  of  health.  It  averaged  0.76  for  the  54  cases 
grouped  below.  As  just  intimated,  it  is  generally  lower  in  the 
early  than  in  the  late  stages  of  the  disease.  In  operative  cases  of 
carcinoma  it  has  been  observed  that  the  regeneration  time  of  the 
hemoglobin  averages  at  least  two-thirds  longer  than  in  other 
diseases  treated  surgically,  and  that  the  loss  of  hemoglobin  after 
operation  is  usually  not  less  than  1 5  per  cent.  Bierfreund  ^  finds 
that  the  percentage  of  hemoglobin  after  the  removal  of  the  tumor 
never  equals  that  found  before  the  operation. 

The  oHgocythemia  is  occasionally  most  striking,  for  in  some 
cases  the  counts  may  range  as  low  as  between  1,000,000  and 
2,000,000,  such  a  degree  of  decrease  apparently  being  most  com- 
monly found  in  septic  cases,  and  in  gastric  cancer.  F.  P.  Henry's 
statement  ^  that  he  has  never  seen  a  case  of  the  latter  disease  in 
which  the  erythrocytes  fell  below  1,500,000  to  the  cubic  milli- 
meter has  been  generally  corroborated,  although  counts  below 
this  figure  have  been  occasionally  reported.  In  one  of  the  cases 
of  cancer  of  the  stomach  included  in  the  table  given  below  the 
count  was  1,001,000  per  cubic  millimeter,  and  the  hemoglobin 
percentage  50. 

Polycythemia  may  occur  as  a  temporary  condition  in  gastric 
and  esophageal  cancer,  as  the  result  of  blood  concentration  due 
to  vomiting,  to  diarrhea,  or  to  lack  of  ingested  fluids.  ^  In  such 
instances  the  number  of  erythrocytes  not  uncommonly  exceeds 
6,000,000  or  7,000,000  per  cubic  millimeter,  and,  exceptionally, 
even  a  higher  figure. 

The  following  table  illustrates  the  alterations  in  the  amount 
of  hemoglobin  and  number  of  erythrocytes,  as  determined  by 
the  examination  of  54  cases  of  various  forms  of  carcinoma. 

Hemoglobin  Percentage.  Erythrocytes  per  cb.  mm. 

From  80-90  in    2  cases.  Above  5,000,000  in    4  cases. 

**     70-80   "  10     '*  From    4,000,000-5,000,000   ''  21      " 
^*     60-70   *'  19      '*  ''      3,000,000-4,000,000   ''  18     " 

"     50—60   "     9     '*  "      2,000,000—3,000,000   "    6 

''    40-50   "     7      ''  "       1,000,000-2,000,000   "    5 

"     30-40   "     5      " 
"     20—30   *'     2     " 

Average  :       58.4  per  cent.  Average  :      3,815,073  per  cb.  mm. 

Maximum:    28.0        **  Maximum:    5,340,000    ^'    "       '^ 

Minimum:    23.0       *'  Minimum:    1,001,000    "    **       " 

1  Langenbeck' s  Archiv. ,  1890-91,  vol.  xli.,  p.  i. 
^AjTchiv.  f.  Verdauungskrankh, ,  1898,  vol.  iv.,  p.  i. 


(( 


MALIGNANT    DISEASE.  387 

In  gastric  cancer  Osier  and  McCrae  ^  report  an  average  of  49.9 
per  cent,  of  hemoglobin  in  52  cases,  and  an  average  erythrocyte 
count  of  3,712,186  in  59  cases.  In  two  cases  the  count  was  less 
than  1,500,000.  An  average  color  index  of  0.63  was  found  in 
this  series. 

Deformities  of  shape  and  of  size  are  marked  in  relation  to  the 
grade  of  the  anemia  which  exists.  Poikilocytes  may  be  quite  as 
numerous  and  as  striking  as  in  true  pernicious  anemia,  while  the 
alterations  affecting  simply  the  size  of  the  cells  tend  toward 
micro-  rather  than  megalocytosis.  Polychromatophiha  and  baso- 
philic degenerative  changes  are  frequently  to  be  seen  in  grave 
cases  with  marked  cachexia. 

Erythroblasts  are  very  common,  especially  in  cancer  with 
decided  cachexia  and  high-grade  anemia,  but  their  occurrence  is 
by  no  means  limited  to  such  cases,  as  they  may  also  be  found  in 
blood  which  shows  but  trifling  quantitative  deterioration.  It  may 
be  stated  as  an  accepted  fact  that  nucleated  erythrocytes  occur  in 
cancer  more  frequently  than  in  any  other  variety  of  secondary 
anemia,  except  that  accompanying  sarcoma. 

Normoblasts  are  generally  found  to  the  exclusion  of  other 
forms,  although  in  an  exceptionally  grave  case  an  occasional 
megaloblast  and  atypical  "  mesoblast "  may  be  encountered. 
The  important  point  to  be  remembered  is  that  cells  of  the  adult, 
normoblastic  type  invariably  predominate,  since  megaloblasts, 
when  present,  are  never  so  numerous  as  normoblasts. 

Leucocytosis  is  a  frequent  but  not  a  constant 

Leucocytes,  feature  of  the  blood-picture  in  carcinosis,  for 
quite  as  many  cases  are  encountered  in  which  the 
number  of  leucocytes  is  normal  as  those  in  which  an  increase 
prevails.  Judging  from  the  statistics  of  patients  treated  in  the 
German  Hospital,  leucocytosis  is  present  in  less  than  one-half  of 
all  forms  of  cancer,  or  in  44.4  per  cent.  In  general  terms,  it  may 
be  said  that  tumors  characterized  by  active  inflammatoiy  changes, 
by  hemorrhage,  by  rapid  growth,  or  by  extensive  metastases  are 
accompanied  by  a  well-marked  leucocyte  increase,  while  non-in- 
flammatory, slowly  developing,  localized  tumors  do  not  raise  the 
count.  Thus,  a  large  carcinoma  of  the  liver  or  kidney,  for  in- 
stance, may  cause  a  leucocytosis  of  30,000  or  40,000  to  the 
cubic  millimeter,  while  a  small,  limited  skin  cancer  may  exist 
without  provoking  the  slightest  increase.  Thorough  extirpation 
of  the  growth  is  followed  by  a  decline  in  the  leucocytosis,  the 
normal  count  being  reached  by  the  time  the  wound  has  entirely 
healed.     Hayem  ^  is  the  authority  for  the  statement  that  in  mam- 

1  "  Cancer  of  the  Stomach,"  London  and  Phila.,  1900,  p.  115. 
2Loc.  cit. 


388 


GENERAL    HEMATOLOGY. 


mary  cancer  recurrence  of  the  growth  after  its  removal  may  be 
detected  by  a  reappearance  of  the  leucocytosis,  which  antedates 
all  other  physical  signs.  The  constancy  of  this  change,  as  well 
as  the  question  of  its  occurrence  in  cancer  involving  other  struc- 
tures, still  remains  to  be  investigated. 

It  seems  reasonable  to  attribute  the  origin  of  cancer  leuco- 
cytosis chiefly  to  the  presence  of  inflammatory  changes  in  the 
tissues  in  the  neighborhood  of  the  growth,  although  in  some  in- 
stances it  seems  possible  that  positive  chemotaxis  may  be  ex- 
cited by  the  absorption  of  toxines  derived  from  the  breaking  down 
of  the  neoplasm  itself  The  strength  of  the  patient's  powers  of 
resistance  as  a  determining  factor  of  the  increase  must  also  be 
taken  into  account  in  this  as  in  other  diseases. 

In  the  writer's  experience,  leucocytosis  is  most  constant  in 
cancer  of  the  breast,  most  striking  in  cancer  of  the  liver,  least 
frequent  in  cancer  of  the  uterus,  and  least  conspicuous  in  cancer 
of  the  stomach.  In  cancer  of  the  esophagus  absence  of  leuco- 
cytosis is  the  rule,  while  in  many  cases  a  decided  leucopenia  may 
exist. 

The  54  cases  on  the  study  of  which  the  above  observations 
are  based  may  be  summarized  as  follows  : 


Seat  of 
Growth. 

Number  of 
Cases. 

Number  and  Percentage 
of  Cases  with  Leucocytosis. 

Average 
Count. 

Maximum 
Count. 

Minimum 
Count. 

Stomach. 

Uterus. 

Rectum. 

Breast. 

Liver. 

23 
10 

8 

7 
6 

9  or  39.1% 
2  or  20.0% 

4  or  50.0% 

5  or  71.4% 
4  or  66.6% 

8,163 

9,380 

10,700 

14,407 
18,733 

14,000 
24,000 
16,000 

3i»5oo 
40,800 

1,000 

4,500 
6,000 
8,000 
8,000 

In  cancer  of  the  stomach  digestion  leucocytosis  is  usually,  though 
by  no  means  invariably,  absent.  The  frequency  with  which  this 
phenomenon  is  absent  is  shown  by  the  following  compilation  of 
the  data  of  various  authorities  who  have  studied  this  question  : 


Author. 


Hoffman 

Osier  and  McCrae. 

Cabot 

Schneyer 

Capps  

Krokiewicz 

Douglas 

Hartung 

Miiller 


Number  of 
Cases. 

Absent. 

24 
I          22 
20 
18 
17 

17 
II 
10 

5 

21 

12           1 

19     ! 
18 

15 
13 

6 

10        ' 

5 

144 

119 

Present. 


10 
I 

O 

2 

4 

5 
o 
o 


25 


MALIGNANT    DISEASE.  389 

These  figures,  referring  to  144  cases,  show  that  digestion  leu- 
cocytosis  is  absent  in  82.6  per  cent,  of  gastric  carcinomata.  But 
the  presence  of  the  phenomenon  in  practically  two  cases  out  of 
every  ten  is  sufficient  to  weaken  materially  the  former  belief  that 
absence  of  digestion  leucocytosis  is  a  diagnostic  sign  of  this 
disease.  Furthermore,  it  has  also  been  shown  by  Hoffman^  and 
others  that  the  sign  may  be  absent  in  a  number  of  other  diseases 
of  the  stomach,  as  well  as  in  some  apparently  healthy  individuals. 

Differential  counts  usually  show  percentages  of  polynticlear 
neutrophiles  ranging  between  80  and  90,  with  a  corresponding 
decrease  in  the  large  and  small  lymphocytes,  in  cases  with  leu- 
cocytosis, and  not  infrequently  also  in  those  without.  This 
change  is  not  to  be  considered  constant,  since  relatively  high 
percentages  of  lymphocytes,  especially  of  the  large  variety,  have 
occasionally  been  observed.  The  eosinophilcs  are  usually  de- 
creased, or,  indeed,  they  may  be  absent  in  cases  with  pronounced 
leucocytosis  ;  in  a  certain  proportion  of  cases,  in  spite  of  the  ab- 
normally high  leucocyte  count,  their  relative  percentage  remains 
within  the  limits  of  health.  Myelocytes  are  extremely  common, 
small  numbers  of  these  cells  (usually  not  higher  than  a  fraction 
of  one  per  cent.)  occurring  in  at  least  a  majority  of  all  cases  of 
cancer.  The  presence  of  a  few  basophiles  is  sometimes  to  be 
noted,  particularly  often  in  association  with  conspicuously  high 
leucocytoses. 

Sarcoma. 

The  changes  affecting  the  fibrifi,  the  rate  of 
General  coagtilation,  and  the  specific  gravity  of  the  blood 
Features,     are    similar   to    those  prevailing  in  cancer,  and 

therefore  require  no  further  mention. 
In  contrast  to  the  hyperglycemia  of  carcinoma,  the  researches 
of  Trinkler,  above  referred  to,  tend  to  show  that  in  sarcoma  no 
increase  above  normal  in  the  amount  of  sugar  in  the  blood  can 
be  detected.  Bacteriological  examinations  of  the  blood  have  thus 
far  given  no  definite  results. 

The  changes  in  the  hemoglobin  and  erythro- 

Hemoglobin    cytes  are  not  materially  different  from  those  found 

AND  in  cancer,  for  the  genesis  of  the  blood  deteriora- 

Erythrocytes.  tion  is  doubtless  similar  in  all  forms  of  malignant 

disease.     Some  authors  believe  that  the  anemia 

tends  to  reach  a  higher  degree  in  sarcoma  than  in   carcinoma, 

but  the  truth  of  this  contention  certainly  does  not  appear  to  be 

indisputably  estabhshed.     In  the  writer's    experience,    unfortu- 

^Zeitschr,  f.  klin.  Med.,  1898,  vol.  xxxiii.,  p.  460. 


390  GENERAL    HEMATOLOGY. 

nately  most  limited  in  so  far  as  it  relates  to  sarcoma,  the  inten- 
sity of  the  anemia  is  practically  similar  in  both  these  forms  of 
neoplasms,  or,  if  anything,  somewhat  more  striking  in  cancer, 
both  individually  and  on  the  average.  In  a  series  of  14  cases  of 
sarcoma  the  hemoglobin  averaged  63.5  per  cent,  ranging  from  a 
minimum  of  42  to  a  maximum  of  83  per  cent.  ;  and  the  average 
count  of  the  erythrocytes  was  3,966,714  per  cubic  millimeter, 
with  2,510,000  and  5,400,000  as  the  lowest  and  highest  counts, 
respectively.  The  color  index  in  these  cases  averaged  0.80.  The 
hemoglobin  percentage  ranged  thus  :  80—90  in  2 ;  70—80  in 
3  ;  60-70  in  2  ;  50-60  in  4  ;  and  40-50  in  3  cases.  The  er>^th- 
rocyte  count  was  as  follows  :  above  5,000,000  in  2  ;  4,000,- 
000-5,000,000  in  4  ;  3,000,000-4,000,000  in  7  ;  and  2,000,000- 
3,000,000  in  a  single  case. 

Poikilocytes,  micro-  and  megalocytes  (particularly  the  former), 
and  atypically  stained  cells  are  common  in  cases  with  pronounced 
anemia,  and  in  such  instances  er^^throblasts,  the  majority  of  which 
are  always  normoblasts,  are  also  to  be  looked  for. 

Leucocytosis,  while  inconstant  in  sarcoma,  is 

Leucocytes,  without  doubt  more  frequently  associated  with 
this  lesion  than  with  carcinoma.  Statistics  have 
also  been  advanced  to  demonstrate  that  the  counts  range 
higher  than  in  cancer,  but  the  cases  on  record  are  still  far  too 
few  to  warrant  this  conclusion.  The  behavior  of  the  leucocytes 
in  both  forms  of  malignant  disease  is  probably  influenced  by  the 
same  group  of  factors.  In  the  cases  summarized  in  the  preced- 
ing pages,  leucocytosis  was  found  in  24  of  the  54  carcinomata, 
or  in  44.4  per  cent.,  and  in  9  of  the  14  sarcomata,  or  in  64.2  per 
cent.  In  the  latter  the  counts  varied  between  7,000  and  40,000, 
and  averaged  13,276  per  cubic  millimeter.  They  ranged  as  fol- 
lows :  5,000-10,000  in  4;  10,000-15,000  in  7  ;  15,000-20,000 
in  I  ;  and  above  20,000  in  2  cases. 

The  increase  usually  involves  a  large  absolute  and  relative 
gain  in  the  polymiclcar  neutropJiiles,  at  the  expense  of  the  lyvipJio- 
cytes,  although  in  an  occasional  instance  the  latter  reach  a  dispro- 
portionately high  percentage,  while  the  former  decline  to  a  sub- 
normal figure.  It  may  be  added  that  either  of  these  differential 
changes  may  also  occur  in  the  absence  of  an  increase  in  the  total 
number  of  leucocytes.  The  percentage  of  cosinopliiles  is  usually 
subnormal,  and  not  infrequently  these  cells  may  be  searched  for 
in  vain.  Rarely,  marked  eosinophilia  has  been  reported,  by  com- 
petent authorities,  in  sarcomata  with  bone  metastases,  but  such 
findings  are  by  no  means  constant.  In  the  six  cases  of  osteosar- 
comata  of  which  the  writer  has  reliable  differential  count  records, 


MALIGNANT    DISEASE.  39 1 

the  eosinophiles  were  absent  in  5,  while  in  the  sixth  their  relative 
percentage  was  but  0.5,  in  a  total  leucocyte  count  of  10,000  per 
cubic  millimeter.  Small  numbers  of  myelocytes  are  to  be  ob- 
served as  frequently  as  not,  these  cells  being  about  as  common 
and  as  numerous  as  they  are  in  cancer — a  remark  which  is  also 
true  of  basop Idles. 

The  clinical  resemblance  between  certain  forms 
Diagnosis,  of  malignant  disease  (especially  those  in  which 
the  lesion  remains  obscure  or  undemonstrable) 
and  pernicious  anemia  is  often  very  close,  on  account  of  the 
striking  degree  of  cachexia  apparent  in  both.  But  the  blood 
changes  found  in  these  two  conditions,  although  similar  in  some 
respects,  are  sufficiently  characteristic  to  afford  the  necessary 
diagnostic  clues.  These  differences,  already  referred  to  in  a  pre- 
ceding section,  may,  for  the  sake  of  emphasis,  be  expressed  as 
follows  : 

Malignayit  Disease.  Pernicious  Anemia. 

Color  index  usually  moderately     Color     index    almost     always 

low.  high. 

Oligocythemia  usually  marked.     Oligocythemia    invariably    ex- 
treme. 
Tendency  toward  microcytosis.       Tendency     toward    megalocy- 

tosis. 
Erythroblasts  common,  normo-     Erythroblasts  constant,   mega- 
blasts  always  predominating.  loblasts  always  predominat- 
ing. 
Leucocytosis  common.                     Leucocytosis  rare. 
Lymphocytosis  rare.                         Lymphocytosis  common. 

It  is  to  be  noted  that  of  the  above  changes,  but  one  is  charac- 
teristic— the  invariable  predominance  of  megaloblastic  cells  in 
pernicious  anemia  and  their  minority  or  absence  in  those  cases  of 
mahgnant  disease  in  which  nucleated  erythrocytes  are  found. 

Should  a  doubt  arise  as  to  whether  a  tumor  is  benign  or  ma- 
lignant in  character,  the  fact  is  to  be  remembered  that  the  pres- 
ence of  a  persistent  leucocytosis,  especially  if  accompanied  by 
anemia,  is  decidedly  in  favor  of  its  malignancy.  Should  it  be 
necessary  to  distinguish  between  a  mahgnant  growth  and  an 
obscure  pus  focus  with  sepsis,  the  blood  examination,  aside  from 
culturing,  is  useless,  since  both  leucocytosis  and  hyperinosis  may 
or  may  not  exist  in  either  condition  ;  if,  however,  bacteriological 
findings  are  positive,  the  existence  of  a  septicemia  is  obvious. 

As  a  means  of  differentiating  carcinomata  and  sarcomata,  the 
chemical  examination  of  the  blood  for  sugar  should  prove  of  the 
greatest  clinical  value,  if  further  research  substantiates  the  claims 


392  GENERAL    HEMATOLOGY. 

made  that  hyperglycemia  is  constant  in  the  first,  and  absent  in 
the  second,  type  of  neoplasms. 

As  a  means  of  distinguishing  gastric  cancer  from  gastric  ulcei^ 
the  blood  count  is  unfortunately  of  doubtful  utility.  The  pres- 
ence of  a  persistent,  well-marked  leucocytosis  is  a  ver}^  significant 
sign  of  cancer,  since  in  ulcer  the  count  is  not  increased,  except 
as  the  result  of  hemorrhage,  perforation,  or  digestion.  On  the 
other  hand,  an  absence  of  leucocytosis  is  of  no  value  in  determin- 
ing which  condition  is  present,  owing  to  the  fact  that  no  increase 
occurs  in  a  large  proportion  of  stomach  cancers.  Recent  inves- 
tigations have  fully  corroborated  Lowit's  view,  that  the  absence 
of  digestion  leucocytosis  in  gastric  cancer  has  about  the  same 
diagnostic  value  as  the  absence  of  hydrochloric  acid  and  the 
presence  of  lactic  acid. 

The  chief  points  of  distinction  in  the  blood-pictures  associated 
with  the  two  diseases  in  question  are  illustrated  by  this  table  : 

Gastric  Cancer.  Gastric  Ulcer. 

Anemia  usually  marked.  Anemia  usually    moderate,   ex- 

Erythroblasts  common.  cept  after  hemorrhage. 

Leucocytosis  common.  Eiythroblasts  rare. 

Absence  of  digestive  leucocy-     Leucocytosis  rare. 

tosis  the  rule.  Absence  of  digestive  leucocytosis 

the  exception. 

If  the  diagnosis  lies  between  carcinoma,  amyloid  disease,  gum- 
ma, and  echinococcus  of  the  liver,  the  presence  of  a  leucocytosis 
suggests  the  former  ;  should  it  lie  between  cancer  and  hypertrophic 
cirrhosis  of  the  liver,  high  leucocytosis  (30,000  or  more)  is 
strongly  in  favor  of  the  former,  since  although  the  leucocytes 
may  be  increased  moderately  in  this  variety  of  cirrhosis,  they  do 
not  reach  a  strikingly  high  figure.  Hyperinosis,  if  present,  is  also 
a  sign  suggestive  of  cancer,  rather  than  of  these  other  liver  dis- 
eases. 

XXXVIII.     MALIGNANT  ENDOCARDITIS. 

The  blood  changes  in  malignant  or  ulcerative 
General       endocarditis  are  essentially  those  of  a  grave  sep- 
Features.      ticemia,  described  elsewhere,  and  do  not,  there- 
fore, require  extended  consideration  in  this  place. 
According  to  the  studies  of  Grawitz,^  Kraus,^  Sittman,^  Kijh- 
nau,*  James  and  Tuttle,^  Thayer  and  Lazear/  and  others,  the 

1  Charite- Annal. ,  1894,  vol.  xix.,  p.  154. 

^Zeitschr.  f.  Heilk.,  1S96,  vol.  xvii.,  p.  117. 

3Deut.  Archiv.  f.  klin.  Med.,  1894,  vol.  liii.,  p.  323. 

*Zeitschr.  f.  Hyg.  u.  Infectionskr. ,  1S97,  vol.  xxv.,  p.  492. 

5,Med.  &  Surg.  Report  of   the  Presbyterian  Hosp.,  N.  Y.,  1898,  vol.  iii.,  p.  44. 

^Jcurn.  of  Exper.  Med.,  1899,  vol.  iv.,  p.  81. 


MALIGNANT    ENDOCARDITIS. 


393 


chances  of  securing  definite  results  from  bacteriological  examina- 
tion of  the  blood  are  fairly  good  in  this  disease.  An  analysis  of 
these  authors'  work  shows  that  various  micro-organisms,  notably 
pneumococci,  gonococci,  streptococci,  and  staphylococci  are 
demonstrable  by  culture  of  the  peripheral  blood  in  about  one 

case  in  every  three.  . 

The  loss  of  hemoglobin  and   erythrocytes  is 

Hemoglobin    likely    to  be  marked,  and,  in    acute    cases,  ex- 
AND  tremely  rapid  and  often  most  excessive— some- 

Erythrocytes.  times  as  great  as  in  typical  pernicious  anemia. 
Structural  degenerative  changes  are  common,  as 
in  any  severe  anemia,  and  in  many  acute  cases  hemoglobinemia 
may  be  observed.  As  a  rule,  the  loss  of  hemoglobin  and  eryth- 
rocytes is  not  markedly  disproportionate,  so  that  moderately 
subnormal  color  indices  are  commonest.  r        .^  ^■ 

The  following  counts,  by  Dr.  Uhle,  of  a  profoundly  septic 
patient  at  the  German  Hospital,  illustrate  the  striking  degree  of 
anemia,  as  well  as  the  intermittent  and  moderate  leucocytosis 
which  may  develop  in  a  grave  case  : 


Date. 


II-  4-99 

11-  8-99 
II-II-99 
11-16-99 
11-20-99 
11-25-99 

12-  1-99 
12-  5-99 
12-16-99 
12-27-99 

I-  5-00 

I-II-OO 


Hemoglobin  Percentage.  I  Erythrocytes  percb.  mm. 


30 
26 

30 
28 

19 
24 

25 

35 
41 
36 
50 
38 


1,590,000 
1,243,000 
2,010,000 
1,810,000 
2,130,000 
2,170,000 
1,710,000 
2,750,000 
3,530,000 
2,330,000 
3,350.000 
2,760,000 


Leucocytes  per  cb.  mm. 

8,000 

8,400 
12,800 

8,000 
14,000 
12,800 

9,600 
16,000 

7,200 

4,800 

8,000 

4,000 


An  increase  in  the  number  of  leucocytes,  more 
Leucocytes,    commonly  moderate  than  marked,  and  character- 
ized by  a  high  percentage  of  polynuclear  nactro- 
philes,  is  the  usual  finding,  except  in  profoundly  >^ept.c  pat.ents 
in  whom  the  count  maybe  normal   or   subnormal  dunng  the 
greater  part  of  the  illness,  as  shown  by  the  above  table.     Ab- 
sence of  leucocytosis  is  not  infrequent  in  thi_s  disease   doubtless 
because  in  a  large  proportion  of  cases  the  f  P-^-^^' .f^;   ^° 
the  poison  predominate.     In  no  other  mfection  is  a  better  illus 
tration  offered  of  the  relationship  between  the  behavior  of  the 
eucocytes,  the  intensity  of  the  disease,  and  the  patient's  powers 
of  reaction      Occasionally,  a  striking  preagonal  increase  develops, 


394  GENERAL    HEMATOLOGY. 

or,  on  the  contrary,  death  may  be  ushered  in  by  a  decided  leuco- 
penia. 

In  many  instances  the  diagnosis  of  malignant 
Diagnosis,  endocarditis  is  materially  facilitated  by  the  blood 
examination,  and  in  some  it  can  be  made  only 
by  this  means.  A  positive  result  from  blood  culturing  at  once 
gives  a  definite  clue  to  the  real  character  of  the  disease,  and  this 
procedure  should  be  undertaken  in  every  doubtful  case.  Malig- 
nant endocarditis  with  marked  constitutional  symptoms  is  perhaps 
most  frequently  confused  with  e7it eric  fever,  and  occasionally  with 
malarial  fever.  Both  of  these  infections  may  be  excluded,  if  a 
leucocytosis  exists,  unless,  of  course,  this  sign  is  obviously  due 
to  some  complication.  It  should  also  be  remembered  that  in 
malignant  endocarditis  the  anemia  develops  early  and  tends  to 
attain  a  marked  degree  with  great  rapidity,  while  in  the  other  two 
fevers  it  does  not  become  striking  until  the  post-febrile  stage  of 
the  disease  is  reached.  No  comment  is  necessary  on  the  value 
of  obtaining  a  positive  serum  reaction  or  of  detecting  the  malarial 
parasite,  as  a  means  of  distinguishing  this  trinity  of  infections. 

XXXIX.      MALTA   FEVER. 

Most  cases  are  accompanied  by  a  moderate,  progressive  second- 
ary afiemia,  becoming  most  marked  at  about  the  end  of  the  febrile 
period,  and  involving,  according  to  Bruce, ^  an  average  loss  of 
about  1,500,000  erythrocytes  to  the  cubic  millimeter.  The  most 
severe  anemia  is  found  in  cases  complicated  by  profuse  epistaxis 
and  hemorrhage  from  the  bowel,  but  those  in  which  these  symp- 
toms are  absent  may  show  simply  a  slight  oligochromemia,  as 
demonstrated  by  a  case  studied  by  Musser  and  Sailer.^  Frank 
leucocytosis  does  not  develop,  except  as  the  result  of  hemorrhage, 
but  occasionally  the  number  of  leucocytes  is  slightly  increased — 
to  about  12,000  or  13,000  per  cubic  millimeter.  Charles^  states 
that  during  the  acute  stages  of  the  infection  he  has  found  a 
notable  relative  increase  in  the  large  lymphocytes. 

Bruce  *  has  not  succeeded  in  finding  the  micrococcus  militensis 
by  antemortem  bacteriological  examijiation  of  the  blood,  although 
he  has  obtained  this  organism  in  pure  culture  by  aspiration  of  the 
spleen.  Wright  and  Smith  ^  discovered  that  the  blood  serum  of 
patients  suffering  from  Malta  fever  clumps   cultures  of  Bruce' s 

1  Brit.  Med.  Journ.,  1889,  vol.  i.,  p.  Iioi. 

2  Phila.  Med.  Journ.,  1898,  vol.  ii.,  p.  1408. 
'British  Med.  Journ.,  1898,  vol.  ii.,  p.  607. 

*  Cited  by  Notter  :  Albutt's  "  System  of  Medicine,"  N.  Y.  and  London,  1897, 
vol.  ii.,  p.  472. 

^Lancet,  1897,  vol.  i.,  p.  656. 


MEASLES.  395 

Specific  micrococcus  but  produces  no  agglutination  of  the  bacil- 
lus typhosus.  The  diagnostic  value  of  this  serum  test  in  dif- 
ferentiating Malta  and  enteric  fevers  has  since  been  corroborated 
by  the  reports  of  Aldridge/  Musser  and  Sailer,^  Kretz,^  Cox,'^  and 
others.  A  I  :  50  dilution  with  a  thirty-minute  time  limit  appears 
to  give  the  most  satisfactory  results. 

XL.     MEASLES. 

The  amount  of  fibrin  is  either  normal  or  de- 
General       creased,  except  in  the  event  of  a  marked  inflam- 
Features.      matory  complication,  which  may  produce  hyper- 
inosis.     The  blood  plaques  are  decreased  in  num- 
ber during  the  febrile  period. 

A  peculiar  bacillus  has  been  isolated  from  the  blood  of  6  cases 
of  measles,  by  Arsamaskoff,^  but  specificity  is  not  unreservedly 
claimed  for  it.  The  organism  in  question  measures  about  3  /^  in 
length,  and  is  almost  as  broad  as  the  Eberth  bacillus  ;  it  may  de- 
velop into  club  forms  in  cultures  made  from  the  circulating  blood. 
Inoculation  experiments  with  animals  gave  negative  results. 
Protozoa  of  undetermined  character  have  been  detected  in  the 
blood  by  Weber.^ 

The    hemoglobin  and  erythrocytes  are  prac- 
Hemoglobin   tically  unchanged  in  typical  cases.     When  a  de- 
AND  crease  does  occur,  it  is  trifling,  amounting  at  the 

Erythrocytes,  most  to  a  loss  of  from  250,000  to  500,000  cor- 
puscles, and  of  about  15  or  20  per  cent,  of  hem- 
oglobin. The  great  majority  of  cases  have  counts  of  5,000,000 
cells  to  the  cubic  millimeter.  Qualitative  changes  in  the  erythro- 
cytes are  absent. 

In  the  uncompHcated  case  of  measles  the  num- 
Leucocytes.  ber  of  leucocytes  is  either  normal  or  subnormal. 
The  latter  change  is  very  common,  the  decrease 
of  leucocytes  being  most  marked  at  the  height  of  the  fever  dur- 
ing the  stage  of  eruption,  and  their  number  again  reaching  nor- 
mal coincidentally  with  the  fading  of  the  eruption  and  the  begin- 
ning of  desquamation.  The  count  may  fall  to  3,000  or  4,000  per 
cubic  millimeter  during  the  period  of  maximum  temperature. 
Combe  ^  believes  that  leucopenia  is  constant  in  all  uncomplicated 
cases,  and  that  the  diminution  in  the  number  of  cells  amounts  to 

^Lancet,  1898,  vol.  i.,  p.  1394. 
2Loc.  cit. 

3 Lancet,  1898,  vol.  i.,  p.  221. 
<Phila.  Med.  Jour.,  1899,  vol.  iv.,  p.  491. 

sBolnitsch.  Gaz.    Botkina,   1898.     Abst.,   Am.   Year  Book  of  Med.   and  Surg., 
1900,  p.  317. 

eCentralbl.  f.  Bakt.  u.  Parasit.,  1897,  vol.  xxi.,  p.  286. 
7  Archiv.  de  med.  des  enf.,  1899,  vol.  ii.,  p.  345. 


396  GENERAL    HEMATOLOGY. 

at  least  one-half  the  normal  number ;  he  finds  that  the  decrease 
begins  during  the  last  two  days  of  the  inv^asion  period,  and  per- 
sists through  the  stage  of  exanthem.  This  author  also  found  a 
striking  degree  of  relative  lymphocytosis,  first  developing  during 
the  early  days  of  the  eruption.  All  cases,  however,  do  not  show 
this  increase  in  mononuclear  forms,  for  in  some  the  relative  per- 
centages of  the  different  varieties  of  leucocytes  remain  as  in 
health.  The  cosinopliilcs  are  usually  either  diminished  or  else 
entirely  absent  during  the  febrile  period  of  the  disease  ;  occasion- 
ally they  reach  a  high  normal  standard,  but  are  not  increased,  as 
in  scarlet  fever. 

Should  leucocytosis  develop,  it  should  be  attributed  to  some 
acute  inflammatory  complication,  such  as  broncho-pneumonia, 
croupous  pneumonia,  or  severe  bronchitis. 

In  cases  with  anomalous  symptoms  the  exist- 

DiAGNOSis.  ence  of  scarlet  fever  may  often  be  excluded  by 
the  absence  of  leucocytosis.  Absence  of  increase 
in  fibrin  and  eosinophiles  is  also  suggestive  in  ruHng  out  this 
infection.  If  the  diagnosis  lies  between  measles  and  sypliilitic 
roseola,  the  absence  of  leucocytosis  points  to  the  former.  The 
initial  stage  of  variola  has  been  mistaken  for  measles,  but  the 
blood  examination  is  of  no  aid  in  differentiating  these  tv/o  condi- 
tions, as  leucocytosis  is  not  found  in  small-pox  at  this  stage  of 
its  development.  Rotheln  does  not  give  rise  to  blood  changes 
distinguishable  from  those  of  true  measles. 

XLI.     MENINGITIS. 

The  condition  of  the  hemoglobin  and  erythro- 

Hemoglobin    cytes  has  not    been  extensively  studied  in  this 

AND  disease,  but  so  far  as  the  data  at  present  avail- 

Erythrocytes.  able  show,  the  only  notable  change  to  be  observed 

consists  in  a  moderate  oligochromemia.       This 

change,  however,  is  inconstant,  for  as  a  rule  both  the  number  of 

corpuscles  and  their  hemoglobin  value  are  normal,  or,  perhaps, 

somewhat  above  normal. 

These  statements,  as  well  as  those  relating  to  the  leucocytes, 
apply  to  the  various  non-tuberculous  inflammations  of  the  cerebral 
and  spinal  pia-arachnoid  and  dura  mater,  acute  leptomeningitis  and 
pachymeningitis,  and  epidemic  cerebro-spinal  meningitis.  The 
blood  changes  associated  with  tuberculous  meningitis  are  described 
elsewhere.     (See  "Tuberculosis.") 

Well-defined  leucocytosis  is  found  in  the  great 
Leucocytes,    majority  of  instances,  the  counts  usually  ranging 
in  excess  of  20,000  to  the  cubic  millimeter,  tend- 
ing to  attain  highest  figures  in  purulent  meningitides. 


MENINGITIS.  397 

Forty-seven  cases  of  various  non-tuberculous  meningeal  in- 
flammations have  been  observed  by  Williams  and  by  Cabot/  in 
all  but  two  of  which  the  leucocytes  at  the  first  examinations 
numbered  more  than  10,000  to  the  cubic  millimeter,  and  in  the 
individual  case  as  high  as  40,000  and  50,000.  The  two  instances 
in  which  the  first  counts  failed  to  show  leucocytosis  were  cases 
of  epidemic  cerebro-spinal  meningitis,  36  of  which  were  included 
in  the  entire  series. 

The  myth,  still  entertained  to  some  extent,  that  tuberculous 
and  non-tuberculous  meningitis  differ  in  that  the  former  does  not 
cause  leucocytosis,  should  have  been  dispelled  long  ago.  Thus, 
while  Tiirk  ^  found  this  sign  in  32  out  of  35  (or  91.4  per  cent.) 
counts  in  non-tuberculous  cases,  he  also  noted  it  in  four  out  of  eight 
counts  in  the  tuberculous  form,  the  maximum  estimate  in  the 
latter  being  20,800  cells  per  cubic  millimeter.  Rieder^  has  re- 
ported a  count  of  14,400  in  one  case  of  tuberculous  meningitis, 
and  in  another,  7,800  and  5,900  cells;  leucocytosis  was  con- 
stant in  this  author's  ten  counts  in  non-tuberculous  cases, 
the  maximum  being  29,300.  Examples  of  this  sort  could  be 
still  further  multiplied  to  demonstrate' that  leucocytosis  in  tuber- 
culous meningitis,  although  infrequent,  nevertheless  does  occur 
at  times. 

The  most  common  differential  change  consists  in  an  absolute 
and  relative  increase  in  the  polynuclear  neutrophiles^  this  alteration 
tending  to  become  most  striking  when  the  total  leucocyte  count 
is  excessively  high.  In  cases  with  a  normal  count,  or  with  only 
a  moderate  increase,  Tiirk  observed  a  relatively  high  percentage 
of  large  lymphocytes  and  transitional  forms,  and  he  has  further 
called  attention  to  the  fact  that  the  eosinophiles  are  either  absent 
or  decreased  to  a  small  fraction  of  one  per  cent,  in  practically 
every  count,  irrespective  of  the  presence  or  absence  of  an  increase 
in  the  total  number  of  leucocytes. 

Between  tuberculous  and  non-tub ercjilotis  men- 

DiAGNOSis.      ingitis,  an  absence  of  leucocytosis  strongly  sug- 
gests  the   former,   although  the  presence    of  a 
leucocytosis  does  not  of  necessity  exclude  it. 

Epidemic  cerebro-spinal  meningitis  sometimes  resembles  such 
infections  as  enteric  fever,  typhus  fever,  pneumonia,  and  malignant 
forms  of  variola.  In  attempting  these  diagnoses,  the  presence  of 
a  leucocytosis  almost  invariably  excludes  typhoid,  but  the  be- 
havior of  the  leucocytes  is  of  no  avail  as  a  means  of  differentiating 

1  Loc.  cit. 

2  Lx)c.  cit. 

3  Lx)c.  cit. 


398  GENERAL    HEMATOLOGY. 

pneumonia  and  variola  ;  most  cases  of  typhus  show  a  normal 
number  of  leucocytes,  although  a  few  with  moderate  leucocytosis 
have  been  reported. 

Acute  meningitis  cannot  be  distinguished  by  the  blood  examina- 
tion from  cerebral  hemorrhage  and  abscess,  since  in  all  these  condi- 
tions high  counts  are  the  rule.  Cabot  ^  believes  that  hysteria,  lead 
eficephalopathy,  diabetic  coma,  simstroke,  and  narcotic  or  alcoholic 
hitoxicatioji  can  be  excluded  by  the  presence  of  a  leucocytosis, 
and  that,  should  the  diagnosis  lie  between  meningitis  on  the  one 
hand,  and  uremia  and  post-epileptic  coma  on  the  other,  an  absence 
of  leucocytosis  is  sufficient  to  exclude  meningitis,  although  its 
presence  is  of  no  diagnostic  value.  It  is  possible  that  bacterio- 
logical examination  of  the  blood  may  furnish  definite  information, 
for  Gwyn^  has  succeeded  in  repeatedly  cultivating  the  diplococcus 
meningitidis  intracellularis  from  the  blood  of  a  case  of  epidemic 
cerebro-spinal  fever.  Several  investigators  have  found  pneumo- 
cocci  in  the  blood  in  cases  of  acute  meningitis. 

XLII.     MYXEDEMA. 

Anemia,  involving  chiefly  the  hemoglobin,  is  a  finding  in  per- 
haps four-fifths  of  all  cases,  judging  from  Murray's^  and  Bram- 
well's*  records  of  56  patients.  More  rarely,  high-grade  anemia 
is  found  in  this  condition,  as  in  a  case  examined  by  Le  Breton,^  in 
which  the  loss  of  hemoglobin  amounted  to  45,  and  the  loss  of 
erythrocytes  to  66,  per  cent,  of  the  normal  standard,  with  a  color 
index  of  1.9 1.  This  author,  as  well  as  Kraepelin,^  in  several 
instances  has  observed  a  general  increase  in  the  diameter  of  the 
erythrocytes,  and  the  presence  of  erythroblasts,  but  such  changes 
are  not  ordinarily  encountered. 

The  leticocytes  are  moderately  increased  in  a  small  proportion 
of  patients,  but  never  reach  notably  high  figures ;  in  fully  three- 
fourths  of  cases  their  number  does  not  exceed  the  maximum 
normal  limit.  In  a  case  published  by  Putnam,^  a  small  number 
of  myelocytes  was  found,  but  no  other  differential  changes  of 
special  interest  have  been  reported. 

A  prompt  increase  in  the  hemoglobin  and  eiythrocytes  follows 
the  administration  of  thyroid  extract  in  appropriate  doses,  but,  on 

^  Loc.  cit. 

2 Johns  Hopkins  Hosp.  Bull.,  1 899,  vol.  x.,  p.  1 12. 

3  "Twentieth  Century  Practice  of  Medicine,"  N.  Y.,  1895,  vol.  iv. ,  p.  710. 

*"  Anemia,"  etc.,  London,  1899,  p.  309. 

5  Bull.  Soc.  med.  des  hop.  de  Paris,  1895,  3  s.,  vol.  xii.,  p.  22. 

^Deut.  Archiv.  f.  klin.  Med.,  1892,  vol.  xlix.,  p.  587. 

'Am.  Journ.  of  Med.  Sc,  1893,  vol.  cvi.,  p.  125. 


NEPHRITIS.  399 

the  other  hand,  excessive  thyroidization  rapidly  aggravates  the 
anemia,  according  to  Bramwell/ 

XLIII.     NEPHRITIS. 

Important   contributing   factors  of  the    blood 
General      changes  in  this  condition  are  albuminuria,  hemor- 

Features.  rhage,  circulatory  disturbances,  and  the  character 
of  the  disease  with  which  the  renal  lesion  may  be 
associated.  The  fact  that  so  many  other  circumstances  are  ca- 
pable of  playing  active  etiological  roles  serves  to  explain  the  great 
dissimilarity  of  the  blood-pictures  in  different  nephritides,  and  at 
different  stages  of  the  same  nephritis. 

Marked  albuminuria  produces  in  course  of  time  a  notable  drain 
upon  the  serum  proteids,  and  a  less  conspicuous  deterioration  of 
the  corpuscles,  especially  affecting  their  volume.  By  this  agency, 
therefore,  the  specific  gravity  of  the  whole  blood  is  diminished,  in 
close  relationship  with  the  extent  of  the  drain  produced.  It  is 
still  a  disputed  question  whether  or  not  edema  may  also  be  held 
responsible  for  this  change.  In  cases  with  hematuria  as  a  promi- 
nent symptom,  the  familiar  picture  of  a  post-hemorrhagic  anemia 
may  be  encountered,  and  in  kidney  inflammations  which  accom- 
pany an  acute  infectious  process,  the  effects  of  the  latter  upon 
the  blood  are  to  be  remembered. 

The  amount  oi fibrin  may  be  found  to  be  increased,  especially 
in  contracted  kidney  ;  the  rate  of  coagulation  is,  so  far  as  has  been 
determined,  exceedingly  inconstant. 

Von  Jaksch,^  von  Limbeck,^  and  others  have  drawn  attention 
to  diminished  alkalinity  of  the  blood  as  a  sign  anticipating  and  ac- 
companying uremic  attacks. 

Bacteriological  examination  of  the  blood  proves  negative,  except 
in  the  terminal  stages  of  nephritis,  when  evidences  of  a  general 
circulatoiy  invasion  by  micro-organisms  may  sometimes  be  de- 
tected. Thus,  excluding  this  factor,  James  and  Tuttle  "*  failed  to 
demonstrate  pathogenic  bacteria  in  the  blood  of  6  successive 
chronic  cases  ;  while,  on  the  other  hand,  White  ^  obtained  growths 
of  streptococci  in  3  consecutive  cases  of  chronic  parenchymatous 
nephritis,  on  the  second,  third,  and  fourth  days  before  death, 
respectively,  these  positive  findings  being  attributed  to  terminal 
septicemia. 

^Loc.  cit. 

2  2eitschr.  f.  klin.  Med.,  1887,  vol.  xiii.,  p.  350. 

^Loc.  cit. 

*  Loc.  cit. 

5  Loc.  cit. 


400  GENERAL    HEMATOLOGY. 

In  acute  par£nchy7natous  nephritis  the  hemo- 
Hemoglobin  globin  and  erythrocyte  values  may  remain  per- 
AND  fectly  normal,  or,  as   is  more  usual,  a  moderate 

Erythrocytes,  secondary  anemia  develops,  of  which  a  greatly 
disproportionate  oligochromemia  is  a  notable  fea- 
ture. The  grade  of  the  anemia  is  highest  in  cases  with  marked 
albuminuria  and  hematuria,  but  only  exceptionally  is  a  loss  of 
more  than  2,000,000  cells  noted.  Laache  ^  estimates  the  aver- 
age loss  in  hemoglobin  at  26  per  cent,  and  in  erythrocytes  at  19 
per  cent.,  and  considers  that  the  decrease  is  much  more  severe 
in  acute  than  in  chronic  cases.  Hayem  ^  is  authority  for  the 
statement  that  striking  anemia  develops  only  in  cases  with 
hematuria. 

In  chro7iic  parencJiyniatous  7iepJiritis  most  observers  state  that 
moderate  hemoglobin  and  erythrocyte  decreases  are  the  most 
notable  findings,  but  some  report  severe  anemia  the  grade  of 
which  is  likely  to  be  most  intense  in  cases  with  marked,  persistent 
albuminuria,  and  with  associated  lesions  of  other  organs.  Sor- 
ensen  ^  found  that  the  count  of  er^^throcytes  in  this  form  of  renal 
disease  averaged  4,700,000  to  the  cubic  milHmeter,  but  in  the 
writer's  experience  a  much  more  pronounced  loss  has  been  ob- 
served— an  average  hemoglobin  percentage  of  57.1,  and  an  aver- 
age erythrocyte  count  of  3,971,206  per  cubic  millimeter,  in  a 
series  of  15  cases.  A  synopsis  of  the  examinations  in  these 
cases  shows  the  following  data  : — Hemoglobin  percentage  :  80- 
90  in  I  ;  70-80  in  2  ;  60-70  in  4 ;  50-60  in  3  ;  40-50  in  2  ; 
and  30-40  in  3.  Erythrocyte  counts  :  above  5,000,000  in  2  ; 
4,000,000-5,000,000  in  4  ;  3,000,000-4,000,000  in  8;  2,000,- 
000-300,000  in  I.  The  maximum  hemoglobin  estimate  in  this 
series  was  82,  and  the  minimum  30,  per  cent.;  the  maximum 
number  of  erythrocytes  per  cubic  millimeter  was  5,520,000, 
and  the  minimum  2,270,000.  The  average  color  index  was 
0.71. 

Polycythemia,  masking  the  real  condition  of  the  blood,  is  not 
at  all  uncommon  ;  it  may  arise  from  some  such  cause  as  cyano- 
sis, or  the  sudden  development  of  an  extensive  edema.  Every 
clinician  must  have  been  repeatedly  struck  by  the  evident  dis- 
crepancy between  the  blood  report  and  the  pinched,  waxy,  ne- 
phritic facies. 

In  chrofiic  interstitial  nephritis,  so  long  as  circulatory  disturb- 
ances do  not  exist,  the  condition  of  the  blood  remains  practically 

•  "  Die  Anaemie,"  Christiania,  1883. 

2Loc.  cit. 

^  Cited  by  Grawitz,  loc.  cit. 


NEPHRITIS.  401 


normal,  but  as  soon  as  the  compensatory  hypertrophy  of  the  left 
ventricle  becomes  inadequate,  the  blood  changes  identified  with 
uncompensated  valvular  heart  disease  develop,  and  various  de- 
grees of  apparent  anemia  and  polycythemia  become  evident  irom 
time  to  time.  These  factors,  the  importance  of  which  is  insisted 
upon  by  Grawitz,^  no  doubt  serve  to  explain  most  of  the  blood 
changes  found  in  sclerotic  kidney,  but  it  seems  obvious  that 
neither  the  malnutrition  of  the  patient  nor  the  considerable  hem- 
orrhages from  which  he  often  suffers  should  be  disregarded  as 
possible  causes  of  blood  deterioration. 

All  the  structural  changes  affecting  the  erythrocytes  in  sec- 
ondary anemia  may  occur  in  association  with  any  of  the  preced- 
ing varieties  of  nephritis,  should  the  accompanying  anemia  be 

sufficiently  striking.  r    .  .    1  ^     • 

In  acute  parenchymatoiis  nephritis,  leucocytosis 

Leucocytes,    may  develop  in  the  early  stages  of  the  disease, 

and  persist  for  some  time  after  convalescence  is 

established.      Cabot,^  who  attributes  the  increase  to  the  effects 

of  hemorrhage  and  of  uremia,  found  it  present  m  6  o    his  13 

cases,  the  maximum  count  being  22,000  per  cubic  millimeter. 

In  three  cases,  in  which  these  two  factors  were  excluded,  the 

writer  found  that  the  number  of  leucocytes  was  6,400,  3,200,  and 

8,700,  respectively. 

In  the  15  cases  of  chronic  parenchymatous  nephritis,  above 
mentioned,  the  number  of  leucocytes  averaged  8,626  per  cubic 
millimeter,  the  maximum  being  16,000,  and  the  minimum  4,000. 
Four   of  the  counts  were  in  excess   of  10,000  ;  9  from    5,000- 

10,000;  and  2  below  5,000.  r  -      yc  -  a  ^\.^ 

Chronic  interstitial  nephritis  does   not  of  itself  influence   the 

number  of  leucocytes. 

Uremia  may  or  may  not  be  associated  with  leucocytosis ; 
the  change  is  to  be  noted  in  the  majority  of  nephritides  in 
which   this  complication  supervenes,  but  it  is  by  no  means  con- 

stant 

In'  all  the  above  forms  of  kidney  inflammation,  the  leucocy- 
tosis if  present,  is  of  the  polynuclear  neutrophile  type.  ^ 
'                         The  blood  count  is  of  no  diagnostic  value  in 
Diagnosis,      nephritis,  nor  can  it  always  be  relied  upon  to  in- 
dicate accurately  the  richness  of  the  blood  in  cel- 
lular elements,  owing  to  the  frequent  prevalence  of  factors  which 
cause  dilution  and  inspissation. 


1  Loc.  cit. 
2Loc.  cit. 


26 


402  GENERAL    HEMATOLOGY. 

XLIV.     NERVOUS   AND   MENTAL    DISEASES. 

In  a  single  case  of  febrile  midtiple  nciuitis 
Neuritis.  Cabot  ^  found  a  moderate  degree  of  secondary 
Beri-beri.     anemia,  with  leucocytosis,  the  counts,  8  in  num- 

Neuralgia.    ber,   ranging  from    16,000  to   28,700  per  cubic 

Brain  Tumor,  millimeter,  and  the  latter  figure  being  reached 

during  the  post-febrile  period  of  the  attack.     This 

author  also  noted  a  moderate  anemia  and  leucocytosis  in  4  of  6 

cases  of  alcoholic  7ictiritis,  but  found  the  number  of  leucocytes 

normal  in  2  5  cases  of  phunbic  7ic2iritis. 

Bcri-beri,  according  to  Spencer,^  is  usually  associated  with  a 
well-defined  secondar}^  anemia,  in  some  instances  characterized 
by  striking  qualitative  changes  affecting  the  size  and  shape  of  the 
erythrocytes.  The  leucocytes,  both  in  number  and  in  the  rela- 
tive percentages  of  their  different  varieties,  remain  normal,  ex- 
cept in  the  acute  stages  of  the  infection,  when  an  increase  in  the 
eosinophiles  may  develop.  Fajardo  ^  has  detected  a  spore -form- 
ing, pigment-producing  hematozoon,  and  Rostra  diplobacillus 
in  the  blood  of  beri-beri  patients,  each  of  which  organisms  has 
been  regarded  by  their  respective  discoverer  as  the  specific  cause 
of  the  disease.  Other  investigators,  notably  Affleck,^  have  ob- 
tained negative  results  from  bacteriological  blood  examinations. 

Neuralgia,  whatever  its  seat,  is  capable  of  exciting  neither 
anemia  nor  leucocytosis. 

The  blood  in  brain  tumor  usually  deviates  in  no  manner  from 
the  normal,  although  rarely  a  moderate  leucocytosis  has  been 
observed.  This  is  a  distinct  contrast  to  cerebral  abscess  and  hevi- 
orrhage,  in  both  of  which  conditions  leucocytosis  is  the  general 
rule.  The  condition  of  the  blood  in  incningitis  has  already 
been  described.     (See  page  396.) 

Neurasthenia,     hvpochondriasis,   and    hysteria. 

Functional    while  they  do  not  primarily  serv^e  as  factors  of 

Neuroses.  blood  deterioration,  are  in  some  instances  associ- 
ated with  other  conditions  which  lead  to  moderate 
secondary  anemia,  usually  involving  chiefly  the  hemoglobin,  and 
but  rarely  causing  any  appreciable  diminution  in  the  number  of 
erythrocytes.  But,  as  a  rule,  functional  neurotics  have  normal 
blood,  in  spite  of  their  anemic  appearance.      Luxemberg,^  in  a 

*  Loc.  cit. 

2  Lancet,  1897,  voL  i.,  p.  32. 

^Centralbl.  f.  Bakt.  u.  Tarasit.,  1900,  vol.  xxvii.,  p.  249. 

*  Lancet,  1901,  vol.  i.,  p.  66. 

5  Edinburgh  Med.  Journ.,  1900,  voL  viii.,  p.  33. 
«Centralbl.  f.  inn.  Med.,  1899,  vol.  xx.,  p.  533. 


NERVOUS    AND    MENTAL    DISEASES.  4O3 

study  of  40  cases  of  hysteria  and  neurasthenia,  found  that  poly- 
cythemia was  common,  having  repeatedly  noted  erythrocyte 
counts  as  high  as  6,000,000,  and  even  in  one  instance  7,300,000 
per  cubic  millimeter ;  he  attributes  this  to  vasomotor  changes, 
possibly  due  in  large  part  to  the  effect  of  the  examination  itself. 
Reinert,^  examining  74  cases  of  these  two  forms  of  neurosis, 
found  a  moderate  hemoglobin  diminution  in  many  cases  of  hys- 
teria, but  normal  blood  in  neurasthenia.  In  sexual  neurasthe- 
nia, however,  anemia  is  not  at  all  uncommon,  in  the  writer's 
experience.  MacPhail  ^  speaks  of  the  marked  anemia  usually 
found  in  insane  masturbators,  and  every  clinician  who  has  made 
many  routine  blood  counts  must  have  been  struck  with  the  fact 
that  the  paUid,  pasty  face  of  the  confirmed  masturbator  but  sel- 
dom falsely  reflects  the  state  of  the  sufferer's  blood. 

The  functional  neuroses  are  not  accompanied  by  leucocytosis, 
but,  on  the  other  hand,  in  many  cases  a  decided  leucopenia  is 
present.  In  all  a  relatively  increased  proportion  of  lympho- 
cytes may  frequently  be  observed,  while  in  hysteria  the  num- 
ber of  eosinophiles  may  be  relatively  in  excess  of  the  normal 
standard. 

MacPhail,^  in  a  prize-essay  submitted  to  the 
General  Medico-Psychological  Association  of  Great 
Paresis.       Britain,  in  1884,  concludes  that  these  mental  dis- 

Dementia.  eases  are  in  many  instances  closely  associated 
Melancholia,  with  a  more  or  less  decided  anemia,  although  in 
Mania.  no  sense  can  blood  deterioration  be  regarded  as  a 
factor  of  insanity.  In  general  paresis  this  observer 
found  subnormal  hemoglobin  values,  averaging  about  67  per  cent., 
on  the  patients'  first  admission  to  the  hospital,  but  later,  as  the 
patient  profited  by  the  improved  hygienic  environment,  this  value 
rose,  only  again  to  fall  to  an  average  of  52  per  cent.,  in  the  terminal 
stages  of  the  affection.  The  oligocythemia  steadily  increased  as 
the  disease  progressed,  and  occasionally  reached  in  the  individual 
case  a  minimum  count  of  between  3,000,000  and  4,000,000  eryth- 
rocytes per  cubic  millimeter ;  it  was  more  striking  during  the  active 
and  completely  paretic  stages  than  during  the  intervening  periods 
of  quiescence.  A  well-defined  leucocytosis  was  constant,  and 
many  of  the  counts  made  shortly  before  death  reached  high  figures. 
Capps,"*  in  a  study  of  19  cases,  found  that  the  hemoglobin  averaged 
85  per  cent.,  and  the  erythrocytes  4,789,900  per  cubic  millimeter 

'  Miinch.  med.  Woch.,  1895,  vol.  xlii.,  p.  305. 

2  Journ.  of  Mental  Sc,  1884,  vol.  xxx.,  pp.  378  and  488. 

"^  Loc.  cit. 

*Am.  Journ.  of  Med.  Sc,  1896,  vol.  cxi.,  p.  650. 


404  GENERAL    HEMATOLOGY. 

— figures  which  may  be  compared  with  Smyth's  average  estimates  ^ 
in  40  cases  :  hemoglobin,  68.7  per  cent.,  and  er}'throc>i:es,  4,- 
700,000.  Capps  states  that  the  majority  of  cases  show  a  moder- 
ate leucocytosis,  averaging  an  increase  of  22  per  cent,  in  excess  of 
the  normal  standard,  but  that  in  the  incipient  stages  of  the  disease 
the  number  of  leucocytes  usually  is  not  increased.  An  average 
count  of  8,800  was  noted  by  Somers,-  in  5  cases.  Relatively  high 
percentages  of  polynuclear  neutrophiles,  with  a  diminution  in  the 
small  lymphocvtes,  are  common  differential  changes,  while  the 
relative  numbers  of  large  lymphocytes  and  eosinophils  may  be 
higher  than  normal.  Convulsions  and  apoplectiform  attacks  tend 
to  produce  blood  concentration,  and  therefore  temporarily  in- 
crease the  hemoglobin  and  er^'throcyte  values.  During  and  fol- 
lowing such  seizures,  an  abrupt  rise  in  the  leucocyte  curve, 
characterized  by  a  striking  absolute  and  relative  gain  in  the  large 
lymphoc)i:es,  and,  rarely,  by  the  appearance  of  myelocytes,  was 
observed  by  Capps,  who  has  also  described  a  small  mononuclear 
neutrophilic  leucocyte,  resembling  a  dwarf  myelocyte,  as  peculiar 
to  the  condition  in  question.  (See  page  1 7 1 .  j  Burrows  ^  believes 
that  the  leucocytosis  associated  with  convulsions,  not  only  in 
general  paralysis,  but  in  other  conditions,  bears  a  definite  relation 
to  the  severity  of  the  fit,  and  that  the  increase  is  in  part  the  result 
of  the  muscular  contractions  attending  the  convulsion,  and  in  part 
represents  an  actual  pathological  leucocytosis.  Acute  delirium 
from  any  cause  also  provokes  leucocytosis. 

In  dementia,  according  to  Smyth, ^  both  the  hemoglobin  and 
erythrocytes  are  decidedly  lower  than  in  the  preceding  condition, 
his  averages  for  this  disease  being  53.7  per  cent,  of  hemoglobin, 
and  a  count  of  4,070,000  erj^throcytes,  in  a  series  of  12  cases. 
In  10  cases  of  melancholia  he  found  that  the  hemoglobin  averaged 
69.7  per  cent,  and  the  erythrocytes  4,684,000,  while  Steele,^  in 
35  cases  of  this  disease,  estimated  the  average  hemoglobin  value 
at  75  per  cent,  and  the  average  erj'throcyte  count  at  3,000,000. 
In  acute  mania  anemia  of  the  so-called  "  chlorotic  "  type  usually 
may  be  observed  ;  this  blood  change  becomes  aggravated  by  each 
acute  maniacal  outbreak,  but  after  recover}-  from  these  attacks 
the  deficiency  is  rapidly  restored.  Somers'  ^  leucocyte  counts  in 
19  dements  averaged  10,743,  in  19  melancholies  7,947,  and  in 
19  maniacs  8,315. 

^Journ.  of  Mental  Sc,  1890,  vol.  xxxvi.,  p.  504. 

2  Bull.  X.  Y.  State  Hosp.,  1896. 

'Am.  Joum.  of  Med.  Sc,  1899,  vol.  cxvii.,  p.  503. 

♦  Loc.  cit. 

5  Am.  Joum.  of  Insanity,  1892,  vol.  xlix.,  p.  604. 

*  Loc.  cit. 


OBESITY.  405 

In  epilepsy  a  moderate  anemia  appears  to  be  the 
Epilepsy.      general  rule.     Smyth's  studies^  of  50  cases  show 
Chorea.       an  average  of  62.8  per  cent,  of  hemoglobin,  and 
Tetany.        4,520,000    erythrocytes    per    cubic    millimeter. 
MacPhail  ^  asserts  that  prolonged  attacks  of  ex- 
citement notably  increase  the  anemia,  but  that  the  habitual  ad- 
ministration of  bromides  seems  in  no  manner  to  produce  deleterious 
effects  upon  the  blood.     Furthermore,  this  author  observed  that 
a  close  relationship  can  be  distinguished  between  the  patient's  gain 
in  weight,  the  decrease  in  the  anemia,  and  the  mental  improve- 
ment, and  that  in  patients  who  recovered,  the  regeneration  of  the 
blood  became  practically  complete.      Leucocytosis  does  not  occur 
in  epilepsy,  except  as  the  result  of  a  convulsion.     Kuhlmann,^ 
for  example,  found  the  leucocytes  in  excess  of  normal  but  once  in 
a  study  of  16  cases. 

In  chorea  slight  anemia,  usually  of  the  *'  chlorotic  "  type,  occurs 
with  frequency  but  not  with  constancy,  for  many  cases  habitually 
show  normal  hemoglobin  and  erythrocyte  values.  It  seems 
scarcely  necessary  to  remark  that  the  belief  once  entertained,  that 
blood  deterioration  was  a  causal  factor  of  this  disease,  is  obviously 
erroneous.  Burr,^  in  a  study  of  the  hemoglobin  and  erythrocytes 
in  36  cases,  concludes  that  a  moderate  diminution  in  both  of  these 
elements  is  the  general  finding,  and  that  a  high  grade  of  anemia 
occurs  only  as  the  result  of  some  complication.  The  oligocy- 
themia usually  does  not  exceed  a  loss  of  more  than  1,000,000 
cells  per  cubic  millimeter,  in  uncompHcated  cases.  The  leuco- 
cytes are  not  increased,  but  differential  counts  may  detect  a  rela- 
tively large  percentage  of  eosinophils,  according  to  the  reports 
of  Zappert,*  and  others.  Tetany  is  not  of  itself  a  cause  of  blood 
impoverishment. 

XLV.     OBESITY. 

From  Kisch's  studies  ^  it  is  evident  that  the  hemoglobin  values 
are  notably  high  in  most  corpulent  individuals,  and  in  some  ex- 
cessively increased.  In  79  of  100  cases  of  obesity  examined  by 
this  author,  the  hemoglobin  percentage  exceeded  100,  while  in 
the  remaining  21  moderate  oHgochromemia  was  found.  The 
maximum  reading  in  this  series  was  120  and  the  minimum  55 
per  cent.     Actual  anemia^  however,  is  not  incompatible  with  this 

1  Loc    cit 

2 Bull*.  N.  Y.  State  Hosp.,  1897. 

3 University  Med.  Mag.,  1896,  vol.  ix. ,  p.  188. 

*Zeitschr.  f.  klin.  Med.,  1893,  vol.  xxiii.,  p.  227. 

5  Ibid  ,  1887,  vol.  xii.,  p.  357. 


406  GENERAL    HEMATOLOGY. 

class  of  patients,  as  demonstrated  by  Leichtenstern/  and  by 
Oertel.^  The  latter  also  maintains  that  in  some  instances  true 
plethora  exists,  and  furthermore  professes  to  recognize  two  dis- 
forms  of  obesity,  an  anemic  and  a  plethoric.  Data  regarding  the 
leucocytes  in  this  condition  are  wanting. 

XLVI.     OSTEOMALACIA. 

The  hemoglobin  and  erythrocytes  do  not  exhibit  any  marked 
deviations,  being  in  most  instances  normal,  or  but  moderately  di- 
minished. The  anemia,  when  present,  tends  to  conform  to  the 
so-called  "  chlorotic  type,"  being  characterized  by  a  hemoglobin 
loss  relatively  exceeding  that  of  the  corpuscles. 

The  leucocytes  also  remain  approximately  normal  in  number, 
slight  fluctuations  above  and  below  this  standard  being  the  only 
numerical  change  thus  far  noted.  Relative  lymphocytosis  has 
been  found  by  Ritchie,^  and  by  Tschistowitch,^  while  Neusser  ^ 
and  others  have  observed  in  many  cases  a  moderate  increase  in 
the  eosinophiles,  and  the  presence  of  small  numbers  of  myelo- 
cytes. None  of  these  differential  changes,  however,  are  to  be 
considered  constant  in  this  condition.  According  to  von  Lim- 
beck,^ the  alkalinity  of  the  blood  remains  practically  unal- 
tered, although  von  Jaksch^  formerly  maintained  that  it  was 
considerably  diminished. 

XLVII.     PERICARDIAL    EFFUSION. 

The  Jie)noglobin  and  erythrocytes  remain  normal,  or,  \{  anemia 
is  found,  it  may  be  referred  to  other  coexisting  conditions. 

Leucocytosis  of  the  polynuclear  neutrophile  type  is  practically 
a  constant  change  in  the  non-tuberculous  forms,  but  in  tuber- 
culous pericarditis  the  leucocytes  apparently  do  not  increase. 
From  a  diagnostic  viewpoint,  the  presence  of  a  leucocytosis  is  of 
real  value  in  excluding  the  latter  condition,  as  well  as  cardiac 
dilatation  ;  this  sign  is  also  strong  evidence  against  the  existence 
of  a  serous  pleural  effusion,  which,  if  left-sided,  may  simulate 
pericarditis. 

'  "Untersuch.  u.  d.  Hg-Gehalt  d.  Blutes,"  Leipzig,  1878. 

2 "  Allgem.  Ther.  d.  Kreislaufsstor.,"  Leipzig,  1884.  Also,  Deut.  Archiv.  f. 
klin.  Med.,  1892,  vol.  i.,p.  293. 

3  Edinburgh  Med.  Journ.,  1896,  vol.  xlii.,  p.  208. 

*  Herl.  klin.  Woch.,  1893,  vol.  xxx.,  p.  919. 

5  Wien.  klin.  Woch.,  1892,  vol.  v.,  p.  41, 

^  Loc.  cit. 

'Zeitschr.  f,  klin.  Med.,  1S87,  vol.  xiii.,  p.  350. 


PERITONITIS. 


407 


XLVIII.     PERITONITIS. 

Anemia   is    frequently   found,   the    degree   of 
Hemoglobin    which  largely  depends  upon  the  character  and 
AND  the  chronicity  of  the  inflammation.     In  general 

Erythrocytes,  purulent  peritonitis,  especially  in  cases  of  com- 
paratively long  standing,  the  hemoglobin  and 
erythrocyte  diminution  may  be  excessive — to  between  20  and  30 
per  cent,  for  the  former,  and  to  between  2,000,000  and  3,000,000 
per  cubic  millimeter  for  the  latter.  With  such  an  anemia  as  this 
the  erythrocyte  loss  is  commonly  very  disproportionate  to  that 
of  the  hemoglobin,  so  that  high  color  indices  rule  ;  for  example, 
in  3  of  the  cases  summarized  below,  the  indices  were  1.12,  i.oi, 
and  1. 00,  respectively.  The  several  qualitative  changes  accom- 
panying any  severe  secondary  anemia  are  also  commonly  to  be 
observed.  Serous  peritonitis  has  but  little  effect  in  provoking 
a  cellular  decrease,  although  it  usually  causes  a  slight  but 
definite  oligochromemia,  so  that  in  such  cases  the  color  indices 
are  moderately  subnormal.  On  the  average,  it  may  be  stated 
that  peritonitis  causes  a  loss  of  about  40  per  cent,  of  hemoglobin, 
and  of  20  per  cent,  of  erythrocytes. 

The  following  summary  of  16  cases,  most  of  which  were  ex- 
amined at  the  German  Hospital,  shows  the  grade  of  anemia  pre- 
vailing in  this  disease : 


Hemoglobin 
Percentage. 

Number  of 
Cases. 

Erythrocytes                          Number  of 
PER  CB.  mm.                                Cases. 

From  80-90 

I 

Above  5,000,000 

3 

70-80 

5 

From   4,000,000-5,000,000 

5 

60-70 

4 

**      3,000,000—4,000,000 

6 

50-60 

I 

**       2,000,000-3,000,000 

2 

40-50 

3 

30-40 

I 

Average : 
Maximum 

20-30 

62.1 

:   82.0 

per 

I 
cent. 

Average:       3,970,000  per 
Maximum :    5,670,000    *' 

cb.  mm. 

Minimum 

:    28.0 

l( 

{( 

Minimum:    2,150,000    *' 

11        t( 

The  color  index  for  this  series  averaged  0.78. 

Provided  that  the  patient's  resisting  powers  react 
Leucocytes,  normally,  septic  peritonitis  constantly  causes  a  typ- 
ical leucocytosis,  of  the  polynuclear  neutrophile 
variety.  It  cannot  be  stated  with  certainty  that  the  increase  is 
greater  in  purulent  than  in  serous  inflammations,  for  any  variety 
of  peritonitis,  except  the  tuberculous,  may  provoke  a  striking 
.leucocytosis.  As  already  remarked  in  the  discussion  of  appen- 
dicitis, extension  of  the  process  is  heralded  by  an  abrupt  rise  in 


408  GENERAL   HEMATOLOGY. 

the  leucocyte  curve.  As  in  other  infections,  leucocytosis  may  be 
absent,  or  leucopenia  may  exist,  in  cases  of  a  profound,  crippling 
character.  The  number  of  leucocytes  in  the  preceding  i6  cases 
ranged  as  follows  : 


Leucocytes  per  cb.  mm. 

No, 

.  OF  Cases, 

Above 

45,000 

I 

From 

35,000-45,000 

I 

<( 

25»ooo-35jOoo 

I 

li 

20,000-25,000 

I 

a 

15,000—20,000 

4 

(( 

10,000-15,000 

6 

ii 

5,000-10,000 

I 

Below 

5,000 

I 

Average:       18,875  per 

cb. 

mm. 

Maximum :   46,000    *' 

{ ( 

(( 

Minimum  :      4,400    " 

( ( 

<t 

The  presence  of  leucocytosis  is  sufficient  evi- 
DiAGNOSis.  dence  for  the  exclusion  of  tubcrcidoiis  peritonitis, 
so-called  hysterical  peritonitis,  and  7'Jieinnatisni  of 
the  abdominal  muscles.  This  sign,  however,  cannot  safely  be 
employed  to  differentiate  between  peritonitis  and  acnte  enteritis, 
certain  forms  of  intestinal  obstruction,  and  rupture  of  a  tubal 
pregfiancy  or  of  an  abdominal  aneurisjn,  all  of  which  may  cause 
more  or  less  leucocyte  increase. 

Cabot  ^  regards  the  association  of  marked  leucocytosis  with 
hyperinosis  as  strongly  in  favor  of  a  peritoneal  inflammation 
rather  than  of  such  conditions  as  non-malignant  boivel  obstruction^ 
malignant  disease,  hysteria,  and  phantom  tumors. 

XLIX.      PERTUSSIS, 

In  so  far  as  can  be  learned  from  the  scanty  literature  at  pres- 
ent available,  the  hemoglobiii  and  erytJirocyte  values  remain  normal 
in  this  disease.  Pronounced  increase  in  the  number  of  leucocytes, 
more  marked  than  is  found  in  any  other  non-febrile  lesion  of  the 
respiratory  tract,  is  a  characteristic  finding  in  whooping-cough. 
Frolich  and  Meunier,^  who  originally  determined  this  fact,  found 
in  30  cases  an  average  of  27,800  leucocytes  per  cubic  millimeter, 
the  individual  counts  ranging  from  a  minimum  of  1 5,500  to  a  max- 
imum of  51,150.  De  Amicis  and  Pacchioni^  have  corroborated 
this  observation,  although  they  consider  that  the  increase  is  some- 
what less,  having  found  an  average  count  of  17,943  for  their  cases. 

'  Log.  cit. 

^Compt.  rend.  Soc.  biol.,  Paris,  1898,  los.,  vol.  v.,  p.  103. 

sQinica  Medica,  1899,  vol.  iv.,  p.  103. 


PLEURISY.  409 

The  leucocytosis  develops  during  the  early  stages  of  the  disease, 
before  the  cough  begins,  and  usually  persists  for  some  time  after 
convalescence  is  established.  As  a  general  rule,  it  may  be  stated 
that  the  younger  the  child,  the  more  notable  the  increase. 
Lymphocytosis^  with  a  consequent  diminution  in  the  polynuclear 
neutrophils  and  eosinophiles,  is  a  constant  and  conspicuous  dif- 
ferential change.  This  lymphocytosis,  according  to  Ehrlich,^ 
is  to  be  attributed  to  the  stimulation  and  swelling  of  the  tracheo- 
bronchial lymphatic  glands. 

The  fact  that  a  marked  leucocyte  increase  occurs  in  the  early 
catarrhal  stages  of  the  disease,  antedating  the  development  of  the 
typical  cough,  may  prove  of  diagnostic  significance. 

L.     PLEURISY. 

Serous  Pleurisy. 

In  acute  cases  it  is  customary  to  find  normal 
Hemoglobin     hemoglobin    and  erythrocyte  values,  or,  at  the 
AND  most,   simply   a  moderate    oligochromemia ;    in 

Erythrocytes,  those  of  longer  standing,  with  decided  debility  of 
the  patient,  anemia,  sometimes  of  a  considerable 
degree,  is  not  an  uncommon  finding.  Thus,  in  an  instance  of  this 
sort  the  writer  found  but  38  per  cent,  of  hemoglobin  and  3,300,- 
000  eiythrocytes  per  cubic  millimeter,  together  with  the  corpus- 
cular degenerative  changes  to  be  expected  in  an  anemia  of  this 
intensity.  It  is  to  be  remembered  that  a  rapidly  developing 
pleural  effusion  may  so  concentrate  the  blood  as  to  cause  a  tem- 
porary polycythemia,  disguising  the  actual  quantitative  changes. 
Absence  of  leucocytosis  is  the  general  rule, 
Leucocytes,  probably  for  the  reason  that  almost  all  serous 
pleurisies  are  of  tuberculous  origin.  Exception- 
ally a  moderate,  intermittent  increase  is  found,  chiefly  affecting 
the  polynuclear  neiitrophiles,  and  due  possibly  to  the  influence  of 
some  intercurrent  process,  such  as  a  secondary  pneumococcus  in- 
fection. A  notable  increase  in  the  eosinophiles  may  often  be  found 
in  hemorrhagic  pleural  effusions.  In  children  a  leucocytosis  is 
sometimes  found,  apparently  independent  of  secondary  infections. 
It  is  quite  evident  that  the  behavior  of  the  leucocytes  can  not  be 
used  as  a  means  of  differentiating  tuberculous  from  non-tubercu- 
lous effusions. 

Morse, ^  in  a  study  of  224  examinations  made  in  20  cases, 
comes  to  the  conclusion  that  there  is  no  definite  relation  between 
the  leucocyte  count  and  the  duration  of  the  disease,  the  degree 

1  Loc.  cit. 

2  Am.  Journ.  of  Med.  Sc,  1900,  vol.  cxx.,  p.  658. 


4IO 


GENERAL    HEMATOLOGY. 


of  pyrexia,  the  amount  of  the  effusion,  and  its  increase  and  dim- 
inution. Neither  could  he  determine  that  the  contamination  of 
the  fluid  by  blood  and  by  microscopical  pus  produced  the 
slightest  effect  upon  the  number  of  cells.  In  Morse's  counts  the 
number  of  leucocytes  exceeded  10,000  to  the  cubic  millimeter  in 
5.8  per  cent.,  while  in  Cabot's  99  cases  ^  this  figure  was  exceeded 
in  14. 1  per  cent.,  the  average  count  for  the  latter  being  6,130. 

Purulent  Pleurisy. 

The  changes  in  the  hemoglobin  and  erjthro- 
Hemoglobin    cjtes  do  not  differ  conspicuously  from  those  pre- 
AND  vailing  in  primaiy  serous  pleurisy,  although  evi- 

Erythrocytes.  dences  of  a  decided  anemia  are  to  be  observed 
somewhat  more  frequently. 
In  8  of  the  writer's  10  cases  of  empyema  the  hemoglobin  loss 
exceeded  50  per  cent,  of  the  normal,  38  per  cent,  being  the  min- 
imum, 73  per  cent,  the  maximum,  and  46  per  cent,  the  average, 
estimate.  The  er>^throc}i:es  were  below  2,000,000  to  the  cubic 
millimeter  in  2  instances,  averaging  3,500,000,  with  1,540,000  as 
the  minimum  and  4,600,000  as  the  maximum,  counts. 

Leucocytosis,  ordinarily  of  a  high  grade,  accom- 
Leucocytes.  panics  the  great  majority  of  cases,  the  increase 
involving  mainly  the  polymiclcar  neiitropJiile  cells 
at  the  expense  of  the  lyinplwcytes.  It  is  more  usual  to  find 
the  count  above  than  below  20,000  to  the  cubic  millimeter, 
and  in  an  exceptional  instance  it  may  even  exceed  50,000.  As- 
piration of  the  pus  is  followed  by  a  decline,  and  its  reaccumula- 
tion  by  a  rise,  in  the  leucocyte  cur\^e.  The  extent  of  the  primary 
purulent  accumulation  cannot  be  gauged  with  any  accuracy  by 
the  degree  of  the  leucocyte  increase. 

The  following  counts  in  a  case  of  empyema  examined  at  the 
German  Hospital,  will  serve  to  illustrate  the  high  leucocytosis 
sometimes  seen  in  this  condition  : 


Date. 

Hemoglobin  Per- 

Erythrocytes per 

Leucocytes  per 

centage. 

cb.  mm. 

cb.  mm. 

I-16-OO 

84 

4,460,000 

23,200 

I-17-OO 

88 

5,380,000 

42,400 

I-18-OO 

82 

4,320,000 

45,000 

I-I9-OO 

82 

4,430,000 

40,800 

1-20-00 

83 

4,383.000 

23,320 

I-2I-00 

82 

4,410,000 

44,300 

1-22-00 

81 

4,330,000 

40,600 

1-23-00 

71 

3,985,000 

37,300 

1-24-00 

67 

4,360,000 

53.500 

1-26-00 

83 

4,240,000 

47,100 

1-27-00 

71 

3,480,000 

48,100 

^  Loc.  cit. 


PNEUMONIA.  411 

In  9  out  of  the  other  10  cases  above  noted,  a  leucocyte  in- 
crease was  found,  the  counts  for  the  10  averaging  17,180  and 
ranging  from  8,600  to  3 1 ,600  per  cubic  millimeter. 

The  presence  of  a  well-developed  leucocytosis 

Diagnosis,  points  to  pneumonia  or  empyema,  rather  than  to 
simple  serous  pleurisy,  but  it  does  not  differentiate 
l^etween  these  first  two  conditions.  On  the  other  hand,  an  ab- 
sence of  leucocytosis  does  not  surely  exclude  pneumonia  and 
empyema,  although  it  is  extremely  suggestive  that  neither  exists. 
Malignant  neoplasms  of  the  lungs  and  pleura  also  cause  a  decided 
leucocyte  increase. 

LI.     PNEUMONIA. 

In  the  case  of  average  severity,  coagulation  is 
General       exceedingly    rapid,    and    the    amount    of    fibrin 
Features,      greatly  increased,  the  network  being  dense,  coarse, 
and  formed  with  great  rapidity.     The  hyperinosis 
tends  to  persist  for  some  time  after  the  disappearance  of  the 
pyrexia  and  the  signs  of  lung  involvement.     In  severe  infections, 
occurring  in  individuals  of  good  resisting  powers,  the  change  is 
especially  striking,  but  in  fatal  cases,  overwhelmed  by  the  disease, 
a  fibrin  increase  is  not  observed.      High  temperature  and  exten- 
sive infiltration  of  the  lungs  are  associated  with  marked  hyperi- 
nosis.    In  children  the  specific  gravity  of  the  blood  is   usually 
high  during  the  febrile  period,  falling  to  normal  as  resolution 
takes  place ;  in  cases  with  marked  cyanosis  the  concentration  of 
the  blood  also  raises  its  density.    Attempts  to  apply  the  seriim  test 
in  this  disease  have  thus  far  been  failures,  the  reports  of  those  who 
have  experimented  with  this  reaction  having  shown  that  the  pneu- 
mococci  are  either  wholly  unaffected  by  the  serum  of  pneumonia 
patients,  or  at  the  most,  agglutinate  very  slowly  and  atypically. 
The  diplococcus  pneumonice  is    present   in  the 
Bacteriology,  circulating  blood  in  only  a  small  proportion  of 
cases,  for  the  bacterial  products,  and  not  the  or- 
ganisms themselves,  gain  access  to  the  general  circulation,  as  a 
general  rule.     Positive  bacteriological  findings  are  commonest  in 
those  cases  complicated  by  a  secondary  pneumococcus  infection, 
and  are  always  to  be  regarded  as  a  grave  prognostic  sign. 

Franklin  W.  White,^  in  19  carefully  studied  cases  of  pneumonia, 
obtained  positive  results  in  3  patients,  all  of  whom  died  ;  of  the  16 
negative  cases,  7  proved  fatal.  Sittmann^  found  the  pneumo- 
coccus in  6  out  of  16  cases  examined  by  him,  in  4  cases  by  cul- 

ijourn.  of  Exper.  Med.,  1899,  vol.  iv.,  p.  425. 
SDeut.  Archiv.  f.  klin.  Med.,  1894,  vol.  liii.,  p.  323. 


412  GENERAL    HEMATOLOGY. 

tural  methods,  and  in  2  in  stained  cover-slip  preparations  of  the 
blood  ;  of  these  6  positive  cases,  4  died,  and  of  the  10  negative 
cases,  but  a  single  one  ended  fatally.  Kohn  ^  examined  32  cases, 
obtaining  positive  results  in  9,  of  which  number  7  cases  were 
fatal,  while  the  other  2  finally  recovered  after  a  grave  infection  ; 
of  this  author's  23  negative  cases,  recover}^  took  place  in  8. 
Pieraccini  ^  found  the  pneumococcus  in  the  blood  in  1 1  out  of  28 
cases,  while  Silvestrini  and  Baduel  ^  claim  to  have  cultured  this 
organism  in  15  out  of  16  pneumonia  patients  whom  they  exam- 
ined. These  Italian  observers  found  that  the  number  of  bacteria 
in  the  blood  usually,  but  not  invariably,  stood  in  relation  to  the 
gravity  of  the  infection.  On  the  other  hand,  James  and  Tuttle,* 
in  their  studies  of  12  cases,  2  of  which  were  fatal,  failed  in  every 
instance  to  obtain  positive  findings. 

From  a  study  of  the  above  statistics,  together  with  those  of 
other  investigators  reporting  smaller  series  of  cases,  it  is  to  be 
concluded  that  the  presence  of  the  pneumococcus  in  the  blood  is 
exceedingly  inconstant,  and  that  positive  findings  are  usually  ob- 
tained only  in  grave  or  fatal  cases.  Eight  of  ever}'  ten  cases  with 
pneumococcus  bacteriemia  end  fatally.  Negative  results  from 
blood  culturing,  however,  cannot  be  considered  of  definite  prog- 
nostic value  in  favor  of  the  patient's  recovery. 

During  the  active  stages  of  the  fever  the  hemo- 
Hemoglobin    globin    and    er}'throcytes    are    either  normal  or 
AND  ver\'  slightly  diminished.     But  polycythemia  also 

Erythrocytes,  may  occur,  as  the  result  of  the  fever's  influence 
in  causing  contraction  of  the  peripheral  vessels, 
or  from  cyanosis.  During  the  post-febrile  period  moderately 
low  counts  are  usually  found,  being  due  possibly  to  the  hemo- 
cytolytic  effects  of  the  fever,  and  to  a  dilution  of  the  blood  caused 
by  the  decreased  arterial  tension  which  occurs  at  this  stage  of 
the  illness.  The  loss,  in  the  writer's  experience,  amounts  in  the 
average  case  to  about  20  per  cent,  of  the  normal  number  of  cells, 
with  a  somewhat  greater  hemoglobin  decrease — approximately  35 
per  cent.  In  1 3  cases,  examined  after  the  seventh  day  of  the  dis- 
ease, the  hemoglobin  averaged  66  per  cent.,  being  as  low  as  40 
and  as  high  as  1 10  per  cent,  in  the  individual  case  ;  the  average 
erythrocyte  count  was  3,988,450  per  cubic  millimeter,  ranging 
from  3,200,000  to  5,500,000.  Poikilocytosis,  and  other  struc- 
tural changes  in  the  cells  are  to  be  noted  only  in  severe  cases. 

1  Deut.  med.  Woch.,  1897,  vol.  xxiii.,  p.  136. 

^Centralbl.  f.  allg.  Path.  u.  pathol.  Anat.,  1900,  vol.  xi.,  p.  460. 

3  Ibid.,  p.  447. 

*  Loc.  cit. 


PNEUMONIA.  413 

In  pneumonia,  as  in  other  acute  infections,  the 
Leucocytes,  severity  of  the  infective  process  and  the  intensity 
of  the  reaction  on  the  part  of  the  organism  are 
the  factors  which  determine  the  behavior  of  the  leucocytes.  In 
the  great  majority  of  cases  a  well-marked  leucocytosis  develops 
at  or  soon  after  the  time  of  the  initial  chill,  and  persists  until 
shortly  after  the  temperature  has  fallen  to  normal. 

A  high  leucocytosis  indicates  a  severe  infection  in  an  indi- 
vidual of  strong  resisting  powers.  A  moderate  increase  indicates 
either  a  slight  infection  coupled  with  good  resistance,  or  an  in- 
tense infection  with  an  inadequate  reaction.  Little  or  no  leuco- 
cyte increase  also  suggests  one  of  two  diametrically  opposite  con- 
ditions :  either  an  infection  too  trivial  to  excite  reaction,  or  one  so 
severe  as  to  overpower  the  organism,  stifling  reaction.  Ewing  ^ 
has  found  that,  as  a  rule,  the  increase  is  greater  in  cases  with 
extensive  lung  involvement  than  in  those  with  limited  lesions,  but 
this  parallelism  between  the  degree  of  leucocytosis  and  the  extent 
of  the  pneumonic  process  is  approximate,  and  does  not  always 
hold  good.  In  a  general  sense,  it  applies  only  to  cases  which 
react  well  toward  the  disease.  There  is  no  relationship  between 
the  degree  of  increase  and  the  degree  of  fever  during  the  active 
stages  of  pneumonia. 

In  the  average  well-marked  case  the  number  of  leucocytes 
usually  ranges  between  20,000  and  30,000  per  cubic  millimeter, 
the  latter  figure  being  only  rarely  exceeded,  as,  for  example,  in 
severe  sthenic  cases,  in  which  the  count  may  rise  to  40,000  or 
50,000.  Summing  up  a  total  of  470  cases  reported  by  various 
observers,  we  find  that  the  average  ''first  count"  of  the  leuco- 
cytes, during  the  febrile  stage  of  the  disease,  was  22,693,  this  fig- 
ure applying  to  all  cases,  both  with  and  without  leucocytosis. 
Between  5  and  10  per  cent,  of  all  cases  fail  to  develop  an  increase, 
and  of  these  over  95  per  cent,  end  fatally,  so  that  from  this  fact, 
an  absence  of  leucocytosis  must  be  regarded  as  of  distinctly  un- 
favorable prognosis,  except  in  those  cases  in  which  the  type  of 
the  infection  is  obviously  mild.  The  occurrence  of  a  high  leuco- 
cytosis is  of  no  definite  prognostic  value,  since  it  indicates  simply 
a  marked  infection  and  good  resisting  powers. 

The  following  table  shows  the  range  of  the  leucocytes  in  27 
hospital  cases  of  pneumonia  : 

Above  45,000  in  2  cases. 

From    25,000-30,000  "  I  case. 

''       20,000-25,000  "  8  cases. 

**       15,000—20,000  '^  4     '' 

^N.  Y.  Med.  Journ,,  1893,  vol,  Iviii.,  p.  715. 


414  GENERAL    HEMATOLOGY. 

From  10,000-15,000  in  4  cases. 
**         5,000-10,000  "  7     *' 
Below     5,000  ''  I  case. 

Highest :    53,500  per  cb.  mm. 
Lowest  :       4,000    <<<'<« 
Average:  17,303    **     "       *' 

In  cases  terminating  by  crisis,  the  leucocytes  begin  to  diminish 
either  a  short  time  before  or  after  the  temperature  commences  to 
decline,  the  normal  number  being  reached,  in  most  cases,  within 
twenty-four  or  forty-eight  hours  after  crisis  occurs,  although  in  a 
small  proportion  of  cases  the  decrease  is  much  slower,  the  count 
sometimes  not  reaching  normal  until  a  week  after  the  tempera- 
ture has  dropped.  False  crises,  although  they  may  cause  a  strik- 
ing drop  in  the  temperature,  do  not  cause  a  decline  of  the  leu- 
cocyte curve. 

In  cases  ending  by  lysis,  the  decrease  in  the  number  of  leuco- 
cytes and  the  decline  in  the  temperature  begin  simultaneously, 
but  the  latter  reaches  normal  much  more  rapidly  than  the  former  ; 
the  leucocyte  decrease  progresses  more  gradually  than  in  the 
cases  ending  by  crisis,  and  the  normal  count  is  often  not  reached 
until  a  week  or  ten  days  after  the  temperature  has  fallen  to  the 
normal  figure.  At  the  beginning  of  lysis  a  correspondence  may 
be  distinguished  between  the  diurnal  fluctuations  of  the  temper- 
ature and  leucocyte  cur\'es,  although  no  such  relation  is  apparent 
during  the  febrile  period  of  the  disease. 

It  is  an  interesting  fact  that  in  about  half  of  all  cases,  whether 
ending  by  crisis  or  by  lysis,  the  maximum  count  of  leucocytes  is 
attained  during-  the  period  of  temperature  decline. 

Von  Jaksch's  ^  idea  of  injecting  substances  to  cause  leuco- 
cytosis  in  pneumonia  where  this  phenomenon  was  absent,  hoping 
thereby  to  benefit  the  patient,  has  not  been  attended  by  the  favor- 
able results  which  he  anticipated.  Leucocytosis  is  as  promptly 
induced  in  the  pneumonic  as  in  the  healthy  individual,  by  the 
injection  of  nuclein,  for  example,  but  without  beneficial  effect 
upon  the  patient's  condition,  a  fact  which  must  be  regarded  as 
evidently  signifying  that  an  absence  of  leucocytosis  in  fatal  cases 
is  not  the  cause  of  death,  as  Billings  ^  remarks. 

Hare  ^  has  drawn  attention  to  the  fact  that  while  leucocytosis 
is  checked  by  antipyretics,  it  is  not  arrested  by  cold  sponging,  an 
observation  which  prompts  Cabot  *  to  declare  in  favor  of  the  latter 
method  of  reducing  temperature  in  pneumonia. 

*  Cited  by  Cabot,  loc.  cit. 

2  Johns  Hopkins  Hosp.  Bull.,  1 894,  vol.  v.,  p.  112. 

3  Therapeutic  Gaz.,  1898,  vol.  xii.,  p.  153. 

*  Loc.  cit. 


PNEUMONIA.  415 

The  leucocytosis  of  pneumonia  is  of  the  typical  variety,  that  is, 
it  is  due  to  a  large  absolute  and  relative  increase  in  the  poly- 
nuclear  neutrophileSy  with  a  consequent  relative  decrease  in  lym- 
phocytes. The  proportion  of  eosinophilcs  is  much  reduced,  and 
frequently  these  cells  are  entirely  wanting.  This  is  regarded  as 
an  unfavorable  sign  by  Becker,^  who  states  that  he  has  never 
found  eosinophils  in  fatal  cases.  With  the  decline  of  the  tem- 
perature and  the  fading  away  of  the  leucocytosis,  the  percentage 
of  polymorphous  cells  rapidly  falls  to  normal  or  subnormal,  and 
the  lymphocytes  and  eosinophils  increase  until  they  regain  their 
normal  percentages.  The  latter  cells  usually  begin  to  reappear 
in  the  circulation  a  day  or  two  before  defervescence,  and  in  some 
instances  a  striking  post-febrile  eosinophilia  develops.  In  20 
cases  showing  marked  leucocytosis,  Billings  found  the  following 
averages  :  lymphocytes,  9.6  per  cent.  ;  polynuclear  neutrophils, 
91.2  per  cent.  ;  eosinophils,  0.2  per  cent.  Heim  '^  found  a  simi- 
lar degree  of  polynuclear  neutrophile  increase  in  19  cases.  In 
3  of  Billings'  counts  in  fatal  cases  showing  no  leucocytosis,  it 
was  found  that  the  various  forms  of  leucocytes  remained  in  their 
normal  relative  proportions,  this  fact  apparently  tending  to  show 
that  no  attempt  whatever  was  being  made  to  resist  the  infection, 
such  as  an  increase  in  the  polymorphous  forms  and  a  decrease 
in  the  mononuclears  would  indicate,  even  in  the  absence  of  an 
increase  in  the  total  number  of  leucocytes.  The  leucocytes 
usually  respond  to  the  iodine  reaction,  most  strikingly  in  cases 
with  high  leucocytosis.  In  such  instances  myelocytes  are  gener- 
ally numerous. 

In  the  pneumonias  of  children  the  possibility  of  lymphocytosis 
should  be  remembered,  for  although  a  true  lymphocytosis  is  rare, 
it  sometimes  occurs,  giving  rise  to  false  impressions,  if  clinical 
signs  other  than  the  examination  of  the  blood  are  neglected. 
(See  p.  197.) 

During  the  period  of  fever  the  blood  plaques  are  markedly  de- 
creased in  number,  and  often,  indeed,  altogether  disappear  from 
the  blood,  but  after  the  crisis  they  reappear  in  great  abundance, 
the  fresh  specimen  taken  at  this  time  often  being  flooded  with 
these  bodies. 

In    atypical    cases    the    presence    of    a   well- 

DiAGNOSis.      marked  leucocytosis  is  a  helpful  sign  in  exclud- 
ing   such  conditions   as  serous  pleurisy,   enteric 
fever,  typhus  fever,  malarial  fever,  and  influenza.     In  the  differ- 
entiation of  croupous  from  catai^rhal  pneumonia,  empyema,  and 

'  Deut.  med.  Woch.,  1900,  vol.  xxvi.,  p.  558, 
2  Archiv.  de  med.  des  enf.,  1901,  vol.  iv. ,  p.  21. 


4i6 


GENERAL    HEMATOLOGY. 


acute  meningitis  the  leucocyte  count  furnishes  no  tangible  clue, 
since  it  is  high  in  all  these  conditions  ;  the  same  is  true  of  some 
cases  of  acute  bronchitis.  An  acute  apical  pneumonia,  if  associ- 
ated with  leucocytosis,  is  almost  invariably  to  be  considered  non- 
tuberculous. 

As  previously  stated,  absence  of  leucocytosis  in  a  case  with  well- 
defined  chest  signs  is  of  grave  prognosis,  but  the  presence  of  a 
leucocytosis  is  by  no  means  always  of  good  augury.  Persistence 
of  a  high  leucocyte  count  is  suggestive  either  of  delayed  resolu- 
tion, empyema,  or  gangrene,  and  a  sudden  reestablishment  of  the 
leucocytosis,  after  its  disappearance  at  the  time  of  crisis,  points  to  a 
recurrent  attack  of  the  disease.  Reappearance  of  the  eosinophiles 
or  the  presence  of  circulatory  eosinophilia,  indicates  the  termina- 
tion of  the  acute  phase  of  the  illness. 

Detection  of  the  pneumococcus  in  the  peripheral  circulation  is 
almost  equivalent  to  signing  the  patient's  death-warrant,  although, 
on  the  contrary,  negative  results  from  blood  cultures  are  of  no 
significance. 

LII.     POISONING. 

A  synopsis  of  the  blood  changes  produced  by  various  toxic 
substances  is  given  in  the  following  table,  these  changes  consist- 
ing chiefly  in  hemocytolysis,  methemoglobinemia,  anemia,  poly- 
cythemia, and  leucocytosis. 


Name  of  Poison. 
Alcohol. 
Amyl  nitrite. 
Acetanilid. 
Ammonia. 
Antipyrin. 

Arseniuretted  hydrogen. 
Aspidium. 
Bromine. 
Chloral. 
Chromic  acid. 

Corrosive  metals  and  minerals. 
Ether. 
Guiacol. 


Effects  7ipon  the  Blood. 

Anemia  ;  often  leucocytosis.^ 

Methemoglobinemia.^ 

Methemoglobinemia.^ 

Leucocytosis.^ 

Methemoglobinemia.^ 

Hemoglobinemia.^ 

Hemocytolysis."* 

Methemoglobinemia.*^ 

Leucocytosis.^ 

Methemoglobinemia.^ 

Anemia ;  leucocytosis.^ 

Oligochromemia  ;  leucocytosis.* 

Hemocytolysis  ;  leucocytosis.^ 


^  Cabot  :    loc.  cit. 

2  Grawitz  :  loc.  cit. 

^Miiller:  Deut.  med.  Woch.,  1S87,  vol.  xiii.,  p.  27. 

*  Georgiewsky  :  Beitr.  z.  path.  Anat.  u.  z.  allg.  Path.,  1898,  vol.  xxiv.,  p.  I. 

*  Hayem  :  Compt.  rend.  Soc.  biol.,  Paris,  1886,  vol.  cii.,  p.  69S. 

6  J.  Chalmers  DaCosta  :  Amer.  Surg.  Assn.,  Baltimore,  May  7,  1901. 
'  Wyss :  Deut.  med.  Woch.,  1S94,  vol.  xx.,  p.  296. 


RABIES. 


417 


Hydrocyanic  acid. 
Illuminating  gas. 

Iodine. 
Lead. 

Nitrobenzol. 

Nitroglycerine. 
Opium. 
Phenacetin. 
Phosphorus. 

Potassium  chlorate. 

Potassium  permanganate. 

Ptomaines. 

Pyrodin. 

Pyrogallol. 

Pyrogallic  acid. 

Snake  and  scorpion  venom. 

Sodium  nitrite. 

Tansy. 

Toadstools. 

Toluene. 

Turpentine. 


Methemoglobinemia.^ 
Methemoglobinemia  ;  polycy- 
themia ;  leucocytosis.^ 
Methemoglobinemia.^ 
Anemia  ;    granular     basophilia  ; 

often  leucocytosis.'* 
Methemoglobinemia  ;  megalo- 
blastic anemia.^ 
Methemoglobinemia.^ 
Occasionally  leucocytosis.^ 
Methemoglobinemia.^ 
Polycythemia  ;  occasionally  leu- 

cocytosis.^ 
Methemoglobinemia ;  anemia  ; 

leucocytosis.^ 
Methemoglobinemia.^ 
Leucocytosis.^ 
Hemocytolysis.^^ 
Methemoglobinemia.^ 
Methemoglobinemia.® 
Hemoglobinemia ;  hypervis- 
cosity ^^ ;  leucocytosis.^^ 
Methemoglobinemia.® 
Leucocytosis.^ 
Hemoglobinemia.^ 
Hemoglobinemia.^^ 
Methemoglobinemia.^ 


LIII.     RABIES. 

Courmont  and  Lesieur  ^'  have  recently  determined  that  an  ex- 
cessive increase  in  the  number  oi  poly  nuclear  neutrophilcs  is  a 
constant  change  in  the  blood  of  patients  suffering  from  hydro- 

1  Robert:  **  Lehrb.  d.  Intoxicationen,"  Stuttgart,  1893. 

2  Cabot  :  loc.  cit.  . 
3Hayem  :  Compt.  rend.  Soc.  biol.,  Paris,  1886,  vol.  cii.,  p.  b9». 
^Grawitzand  Hamel :  Deut.  Archiv.  f.  klin.  Med.,  1900,  vol.  Ixvu.,  p.  357. 
sEhrlich  and  Lindenthal  :  Zeitschr.  f.  klin.  Med.,  1896,  vol.  xxx.,  p.  427- 
eGrawitz  :  loc.  cit. 

7Kr6nig  :  Berl.  klin.  Woch.,   1898,  vol.  xxxii.,  p.  998. 

8  Von  Jaksch  :   Deut.  med.  Woch.,  1893,  vol.  xix.,  p.  lo. 

9Bradenburg  :  Berl.  klin.  Woch.,  1895,  vol.  xxxii.,  p.  583. 
JOTallquist:  "  Exper.  Blut.  gizt.  Anemie,"  Berlin,  1900. 

1'  Stengel  :    "  Contributions  from  the  William  Pepper  Laboratory  of  Clinical  Medi- 
cine," Phila.,  1900.  1  •  ^^ 
i2Auche  and  Vaillant :  Journ.  de  Med.  de  Bordeaux,  1901,  vol.  xxxi.,  p.  29. 

13  Vast  :  "  Thdse  de  Paris,"  1889. 

14  Sam.  m6d.,  1901,  vol.  xxi.,  p.  61. 

27 


4i8 


GENERAL    HEMATOLOGY. 


phobia,  and  that  analogous  findings  are  met  with  experimentally 
in  rabid  dogs,  guinea-pigs,  and  rabbits.  The  polynuclear  gain  is 
frequently,  but  not  invariably,  associated  with  an  increase  in  the 
total  number  of  leucocytes.  It  may  amount  to  as  much  as  98 
per  cent.,  and  first  develops  during  the  period  of  incubation,  be- 
coming emphasized  with  the  appearance  of  the  clinical  symptoms 
of  the  affection,  and  reaching  a  maximum  just  before  death. 
The  authors  referred  to  believe  that  an  absence  of  polynucleosis 
is  sufficient  to  rule  out  rabies  in  a  suspected  case,  although  its 
presence  cannot  be  regarded  as  pathognomonic  of  the  disease. 

LIV.    RELAPSING   FEVER. 

The  specific  cause  of  relapsing  fever,  a  spiril- 
Parasitology.  lum  discovered  by  Obermeier  in  1868,^  may  be 
found  in  the  peripheral  blood  of  patients  suffer- 
ing from  this  disease,  only  during  and  shortly  before  the  febrile 
paroxysm,  the  organism  disappearing  from  the  general  circulation 
during  the  interparoxysmal  afebrile  period.     The  number  of  para- 

FlG.   48. 


Spirilla  of  relapsing  fever. 


sites  found  in  a  blood-film  varies  within  wide  limits,  and  does  not 
generally  stand  in  any  definite  parallelism  to  the  severity  of  the 
infection  or  to  the  degree  of  pyrexia. 

Microscopically,  the  spirilla  of  Obermeier  appear  in  the  fresh 
blood  as  delicate,  homogeneous,  thread-like  bodies  twisted  into 
the  form  of  spirals,  occurring  singly  or  in  groups  of  several  or- 


^  Centralbl.  f.  d.  med.  Wissensch.,  1873,  vol.  xi.,  p.  145. 


RELAPSING    FEVER.  4I9 

ganisms,  radiating  from  a  common  center.  ( Fig.  48.)  The 
length  of  the  parasites  varies  from  16  to  40  //,  or  approximately 
from  two  to  six  times  the  size  of  the  normal  erythrocyte.  They 
possess  an  active  vibratile  motility,  exerted  in  the  direction  of 
their  long  axes,  by  virtue  of  which  they  are  propelled  and  con- 
stantly altered  in  shape.  Owing  to  this  characteristic  motility, 
the  presence  of  the  parasites  is  usually  first  betrayed  to  the  ex- 
aminer by  the  whipping  about  of  the  blood  corpuscles  in  their 
immediate  proximity.  The  spirilla  remain  alive  for  only  a  short 
time  after  the  withdrawal  of  the  blood,  and  are  so  extremely 
sensitive  to  external  influences  that  the  addition  even  of  distilled 
water  causes  them  rapidly  to  disappear.  Since  nothing  is  known 
of  their  life  history,  the  cause  of  their  disappearance  from  the 
peripheral  circulation  during  the  intermissions  of  the  disease  is 
not  known. 

Both  Sarnow  ^  and  von  Jaksch  ^  have  called  attention  to  the 
presence  of  certain  refractive  bodies,  similar  to  diplococci,  which 
may  be  found  in  the  blood  during  the  intermission,  provided  that 
another  paroxysm  is  impending.  The  last-named  authority  be- 
lieves that  he  has  observed  the  metamorphosis  of  these  bodies 
into  short  thick  rods  from  which  the  typical  spirilla  eventually 
are  evolved,  and  he  tentatively  regards  them  as  spores  of  the 
latter.  The  views  of  this  investigator  have  not,  however,  been 
generally  accepted  up  to  the  present  time. 

Afanassiew^  has  described,  in  addition  to  the  specific  spirilla, 
peculiar  bacteria  which  he  found  in  the  blood  during  the  parox- 
ysm. The  organisms  in  question  resemble  bacilli  with  rounded 
poles,  and  appeared  to  be  invested  by  non-staining,  hyaline 
sheaths.  Some  of  them  measured  not  more  than  5  or  6/i  in 
length,  while  others  appeared  as  filamentous  threads  fully  10,  12^ 
or  14/i  long,  this  increase  in  size  being  demonstrable  in  the  fresh 
specimen  watched  for  some  time  under  the  microscope.  Afanas- 
siew  asserts  that,  unlike  Obermeier's  spirilla,  the  bodies  may  be 
cultivated  on  bouillon,  gelatine,  agar,  and  blood  serum  ;  he  further 
claims  that  in  three  patients  inoculated  with  a  twenty-four-hour- 
old  bouillon  culture  of  the  organism,  periods  of  pyrexia,  recurring 
at  ten-day  intervals,  were  produced,  and  that  in  the  blood  of  one 
of  the  patients  thus  treated  numerous  bacillary  and  filamentous 
forms  were  discovered.  These  investigations,  as  yet  unconfirmed 
by  other  workers,  are  to  be  regarded  only  in  the  Hght  of  an  in- 
teresting observation. 

'  Inaug.  Dissert.,  Leipzig,  1882. 

2  "Clinical  Diagnosis,"  3d  ed.,  London  and  Phila.,  1897,  p.  50. 

3  Centralbl.  f.  Bakt.  u.  Parasit.,  1899,  vol,  xxv.,  p.  273. 


420  GENERAL    HEMATOLOGY. 

Melanin  granules,  either  free  or  within  the  protoplasm  of  the 
leucocytes,  are  frequently  seen  in  the  blood,  especially  just  after  a 
paroxysm,  and  phagocytes  containing  engulfed  spirilla  may  also 
be  found  at  this  time. 

Teclmique  of  Exainmatioii.  Fresh  specimens  of  blood,  taken 
during  the  paroxysm  from  the  patient's  finger  or  ear,  are  most  suit- 
able for  microscopical  examination.  The  motility  and  finer  struc- 
ture of  the  spirilla  are  seen  most  clearly  with  a  ^^^  inch  oil-immer- 
sion objective,  but  for  making  the  preliminary  search  a  lower  power, 
dry  lens  is  more  convenient,  a  J  or  i  inch  objective  being  useful 
for  this  purpose. 

Dried  films,  fixed  by  one  of  the  chemical  methods  of  fixation 
already  described  (page  62)  may  be  stained  preferably  by  fuch- 
sin,  or  the  method  of  Giinther  (page  86)  may  be  used.  For 
diagnostic  purposes  stained  specimens  are  never  to  be  preferred 
to  the  fresh  blood  film. 

LowentJiar s  Reaction.  The  ingenious  blood  test  devised  by 
Lowenthal  ^  furnishes  a  means  of  recognizing  relapsing  fever  dur- 
ing the  afebrile  period,  when  the  spirilla  cannot  be  detected  in  the 
blood.  It  is  conducted  in  the  following  manner.  A  drop  of 
blood  from  a  suspected  case  is  mixed  with  a  drop  containing 
motile  spirilla,  the  latter  being  taken  from  a  patient  during  the 
paroxysmal  stage  of  the  disease.  The  mixture  thus  made  is 
sealed  between  a  slide  and  cover-glass,  and  incubated  at  body 
temperature  for  half-an-hour,  at  the  end  of  which  time  it  is  ex- 
amined under  the  microscope.  If  the  suspected  case  be  one  of 
relapsing  fever,  the  spirilla  will  have  become  quite  motionless  and 
collected  together  in  irregular  masses,  while  if  the  case  be  one  of 
some  other  disease  the  motility  of  the  parasites  remains  unim- 
paired. A  control  specimen,  prepared  from  normal  and  spirilla- 
containing  blood,  must  always  be  similarly  incubated  and  ex- 
amined with  each  test.  If  no  such  reaction  as  that  described 
occurs  within  a  time  limit  of  two  hours  and  one-half  at  the  most, 
it  is  safe  to  regard  the  suspicious  case  as  one  not  of  relapsing 
fever.  In  35  cases  of  this  disease,  Lowenthal  obtained  about  85 
per  cent,  of  positive  results,  while  in  14  cases  of  fever  due  to 
other  causes  the  reaction  was  uniformly  absent. 

The  reaction,  which  takes  place  in  abortive  and  mild  cases  as 
well  as  in  the  severer  forms  of  the  disease,  is  thought  to  be  de- 
pendent upon  the  presence  in  the  blood  of  specific  bactericidal 
products. 

1  Deut.  med.  Woch.,  1897,  vol.  xxiii.,  p.  560. 


RHEUMATIC    FEVER.  421 

Von  Limbeck,^  quoting  von  Bockmann,  states 
Hemoglobin    that  there  is  a  decrease  in  the  number  of  erythro- 
AND  cytes  and  in  the  hemoglobin  value  in  cases  of  re- 

Erythrocytes.  lapsing  fever,  but  neither  the  mode  of  production 
of  such  an  anemia,  nor  the  exact  morphological 
changes  by  which  it  is  characterized,  have  been  carefully  investi- 
gated, so  far  as  can  be  ascertained.  The  losses  are  observed  to 
occur  during  and  for  a  few  days  after  each  paroxysm,  but  they 
are  partly  compensated  during  the  interparoxysmal  period. 

A  variable  degree  of  increase  in  the  number  of 
Leucocytes,  leucocytes,  often  of  high  grade,  has  been  described 
by  Laptschinski^  as  associated  with  the  paroxys- 
mal stage  of  the  disease,  this  observer  having  noted  that  the 
"coarsely  granular  elements"  were  especially  involved,  and  that 
the  relative  number  of  leucocytes  to  erythrocytes  was  in  some 
instances  as  high  as  i  to  37.  During  the  period  of  intermission 
this  leucocytosis  disappears.  This  author,  as  well  as  von  Bock- 
mann^ and  Heidenrich,*  also  noted  that  the  period  of  maximum 
leucocytosis  was  reached  just  after  the  crisis. 

The  detection  of  the  spirillum  in  the  blood  im- 
DiAGNOSis.  mediately  differentiates  relapsing  fever  from  typhis 
fever,  the  onset  and  initial  symptoms  of  which  not 
infrequently  prove  confusing,  and  it  may  also  be  added  that  in  such 
instances  the  absence  of  this  organism  during  the  stage  of  pyrexia 
is  strong  evidence  for  excluding  the  first-named  disease.  During 
the  afebrile  period,  when  the  symptoms  may  suggest,  for  ex- 
ample, malarial  fever,  Lowenthal's  reaction  should  be  attempted, 
and  the  malarial  parasite  searched  for.  Melanemia,  it  must  be 
recalled,  may  be  encountered  in  both  of  these  infections. 

LV.     RHEUMATIC    FEVER. 

Coagtdation  of  the  blood  takes  place  within  the 
General       normal  time  limit,  or  it  may  be  delayed  consider- 
Features.      ably.      The   amount   of  fibrin    is    markedly  in- 
creased, especially  during  the  most  acute  stages  01 
the  illness.      Contradictory  reports  have  been  made  by  different 
•authors  concerning  the  alkalinity,  some  having  found  it  dimin- 
ished, and  others  having  been   unable  to  detect  any  such  altera- 
tion.    According  to  Hutchinson,^  the  general  consensus  of  opin- 

^  Loc.  cit. 

^Centralbl,  f.  d.  med.  Wissensch,,  1875,  vol.  xiii.,  p.  36. 

3  Loc.  cit. 

'*''Untersuch.  ii.  d.  Par.  d.  Riickfallstyphus,"  Berlin,  1877. 

5  Lancet,  1896,  vol.  i.,  p.  615. 


422  GENERAL    HEMATOLOGY. 

ion  is  against  any  notable  disturbance  of  the  normal  figure.  In 
chronic  articular  rheumatism  with  coexisting  anemia  a  slight  dim- 
inution of  the  alkalinity  is  occasionally  observed. 

The  bactcriolo_^y  of  the  blood  in  this  disease  has  for  many 
years  been  the  object  of  much  careful  study,  but  thus  far  specific 
properties  have  not  been  generally  conceded  to  any  definite  or- 
ganism, although  a  great  number  of  different  bacilli,  streptococci, 
staphylococci,  and  diplococci  have  been  cultivated  from  the  circu- 
lating blood  during  life.  At  the  present  time  the  bacillus  iso- 
lated by  Achalme  *  and  the  diplococcus  of  Trlboulet  ^  are  regarded 
by  many,  especially  by  some  of  the  French  school,  as  possible 
etiological  factors,  if,  indeed,  rheumatic  fever  is  actually  a  bacterial 
disease.  For  a  careful  review  of  the  bacteriology  of  rheumatism 
the  reader  should  consult  the  admirable  brochure,  **  Le  Rhu- 
matisme  articulaire  aigu  en  bacteriologie,"  by  Triboulet  and 
Coyon,  Paris,  1900. 

Few  cases  of  acute  rheumatic  fever  are  unac- 
Hemoglobin    companied    by  anemia,   the    intensity  of  which 
AND  generally  bears  a  fairly  close  relation  to  the  se- 

P2rvthrocvtes.  verity  and  the  duration  of  the  illness.  In  acute 
attacks  of  short  duration  the  hemoglobin  falls  to 
about  70  or  80  per  cent,  and  the  erythrocytes  to  4,000,000,  but 
in  cases  of  longer  standing  the  losses  are  likely  to  be  more  pro- 
nounced, the  count  often  being  not  more  than  3,000,000  or 
thereabouts.  The  color  index  usually  is  moderately  subnor- 
mal, and  may  tend  to  remain  so  after  the  attack,  even  though  the 
rise  normalward  of  the  erythrocyte  count  may  have  become  well 
established.  In  chronic  rheumatism  a  moderate  oligochromemia 
is  usually  the  only  evidence  of  anemia  that  can  be  detected,  un- 
less the  patient  happens  to  be  decidedly  cachectic. 

Cabot's  43  cases  of  acute  rheumatic  fever  ^  showed  an  average 
hemoglobin  estimate  of  67  per  cent.,  and  an  average  erj^throcyte 
count  of  4,400,000  per  cubic  millimeter.  In  the  writer's  experi- 
ence, limited  to  7  cases,  the  anemia  was  found  to  be  much  more 
striking,  for  in  two  the  hemoglobin  estimates  were  26  and  30  per 
cent.,  and  the  counts  1,242,000  and  1,590,000,  respectively. 
These  figures  were  sufficient  to  lower  the  av^erages  for  the  total 
number  to  47.6  per  cent,  for  hemoglobin,  and  3,098,964  per  cubic 
millimeter  for  the  erythrocytes. 

'  Compt.  rend.  Soc.  biol.,  Paris,  1891,  9  s. ,  vol.  iii.,  p.  651.  Ibid.,  1897,  10  s., 
vol.  iv.,  pp.  276  and  locx). 

^  Rev.  de  med.,  Paris,  18S8,  vol.  xviii.,  pp.  189  and  329.  Also,  Triboulet.  Coyon 
and  Zadoc  :   Hull.  Soc.  nied.  des  hop.  de  Paris,  1897,  3  s.,  vol.  xiv.,  p.  1343. 

3  Loc.   cit. 


SCARLET    FEVER.  423 


Should  the  cellular  loss  reach  a  high  grade,  deformities  of 
shape  and  size,  polychromatophilia,  and,  rarely,  nucleated  erythro- 
cytes of  the  normoblastic  type  may  be  observed. 

Leucocytosis  of  the  typical  polynuclear  neutro- 

Leucocytes.  phile  type  is  almost  always  present  during  the 
acute  stages,  but  it  is  found  only  exceptionally  in 
the  subacute  form  of  rheumatism,  and  practically  never  exists  in 
the  chronic  variety.  The  count  does  not  often  exceed  twice  the 
maximum  number  of  cells  found  normally,  but  occasionally  it 
reaches  a  figure  as  high  as  30,000  or  40,000  per  cubic  millimeter 
especially  in  very  acute  cases,  which  as  a  rule  are  associated 
with  the  highest  leucocytoses.  In  Cabot's  cases,  above  referred 
to  the  number  of  leucocytes  averaged  16,800,  and  ranged  from 
4  700  to  39,000.  In  the  writer's  cases  the  maximum  count  was 
^'i  200,  the  minimum  8,000,  and  the  average  I4,857- 

Tiirk^  has  noticed  that  in  many  instances  well-marked  post- 
febrile eosinophilia  develops,  and  that  in  favorable  cases  a  relatively 
high  percentage  of  eosinophiles  persists  during  the  acute  stage 

pyrex    .  ^^^  \^\oo^  changes  are  uncharacteristic,  and  do 

Diagnosis  not  serve  as  a  means  of  differentiating  this  condi- 
tion  from  other  lesions  in  which  the  joint  involve- 
ment and  the  constitutional  manifestations  are  more  or  less  similar. 
Thus  in  acute  gout,  in  multiple  secondary  arthritis,  and  in  septic 
arthritis  due  to  pyemia,  the  same  grade  of  anemia,  leucocytosis, 
and  hyperinosis  may  be  observed. 

LVI.     SCARLET  FEVER. 

In   cases  associated   with  pronounced  anginal 

General      symptoms  and  with  marked  leucocytosis,  coagii- 

Features      lation  of  the  fresh  blood  drop  is  rapid,  and  the 

amount  of  fibrin  decidedly  in  excess  of  normal. 

In  many  cases  a  slight  increase  of  fibrin  is  observed  at  the  period 

of  bednning  desquamation.  . 

The  specific  gravity  is  unchanged  in  the  average  case,  but  in 
those  complicated  by  acute  parenchymatous  nephntis.  in  conse- 
quence of  the  drain  on  the  albuminoids  of  the  blood  thus  pro- 
duced, it  may  fall  to  a  very  low  figure— to  1030,  according  to 
Peiper  and  Hammerschlag.^  In  12  cases  studied  by  van  den 
Bere'  the  specific  gravity  ranged  from  103 1  m  complicated 
cases,  to   1060  in  uncomplicated  cases  of  the  average  severity. 

^Loc.  cit.  ,      ..  -       J  C/^f 

zCentralbl.  f.  klin.  Med.,  1891,  vol.  xii.,  pp.  217  and  S25. 
3  Archiv.  f.  Kinderheilk. ,  1898,  vol.  xxv.,  p.  321. 


424  GENERAL    HEMATOLOGY. 

The  specific  micro-organism  of  scarlet  fever 
Bacteriology,  has  not  yet  been  isolated,  either  from  the  blood 
or  other  tissues,  although  in  recent  years  many 
different  bacteria  have  been  described  as  causative  factors. 
Class  ^  claims  to  have  discovered  in  the  blood  and  throats  of 
scarlet  fever  patients  a  diplococcus,  named  by  him  the  diplococcjis 
scarlatincE,  which  he  considers  specific,  and  this  claim  has  received 
the  support  of  a  number  of  other  investigators,  Gradwohl," 
Jaques,^  and  Page ''  being  among  those  who  found  the  bac- 
terium in  question.  Baginsky  and  Sommerfeld  ^  conclude,  as 
have  some  earlier  writers,  that  the  clinical  features  of  scarlet 
fever  are  due  to  a  general  streptococcus  infection,  having  found 
this  organism  in  the  blood  of  42  fatal  cases.  Class,^  in  a  later 
communication,  hints  that  his  diplococcus  and  Baginsky  and  Som- 
merfeld's  streptococcus  are  identical,  since  the  former  often  de- 
velops streptococcus  forms  in  young  cultures  made  from  the 
blood.  Any  one  who  has  read  Class'  description  of  his  organ- 
ism must  be  struck  with  its  resemblance  to  the  diplococcus  found 
in  scarlet  fever  blood  by  Crajkowski,^  in  1895.  Jehle^  states 
that  he  has  repeatedly  isolated  the  influenza  bacillus  from  the 
blood  of  young  children  ill  with  scarlet  fever.  The  studies  of 
these  investigators,  while  of  the  greatest  interest,  are  scarcely 
conclusive. 

Most  observers  agree  that  the  scarlatinal  infec- 
Hemoglobin    tion,   unless   complicated,   produces    but  trifling 
and  changes  in  the   hemoglobin    and    erythrocytes, 

Erythrocytes,  moderate   anemia  characterized  by  a  dispropor- 
tionate diminution  of  hemoglobin  being  the  gen- 
eral rule  in  the  cases  in  which  any  changes  are  noted. 

Widowitz^  found  that  the  percentage  of  hemoglobin,  normal 
at  the  beginning  of  the  illness,  slowly  diminished  during  the  fe- 
brile period,  in  a  degree  commensurate  to  the  intensity  of  infec- 
tion, and  gradually  returned  to  normal  during  convalescence. 
Pee  "^  noticed,  in  severe  cases,  a  pronounced  **  chloro-anemia," 
characterized  by  notable  pallor  and  variations  in  the  size  of  the 
corpuscles.    Hemoglobinemia  has  also  been  occasionally  observed. 

'  N.  V.  Med.  Record,  1899,  vol.  Ivi.,  p.  330. 
^Phila.  Med.  Journ.,  19CX),  voL  iv.,  p.  688. 
3Ibid.,  p.  552. 

*  Journ.  liost.  Soc.  Med.  Sc,  1899,  vol.  iii.,  p.  344. 
5  Berl.  klin.  Woch.,  1900,  vol.  xxxvii.,  p.  5S8, 
^ Journ.  Am.  Med.  Assn.,  1900,  vol.  xxxv.,  p.  799. 
^Centralbl.  f.  Bakt.  u.  Parasit.,  1895,  vol.  xviii.,  p.  116. 
8  Zeitschr.  f.  Heilk.,  1901,  vol.  xxii.,  p.  190. 

^Jahrb.  f.  Kinderheilk.,  1888,  vol.  xxvii.,  p.  380;  vol.  xxviii.,  p.  25. 
'°Inaug.  Dissert.,  Berlin,  1890. 


SCARLET    FEVER.  425 

The  number  of  erythrocytes  is  generally  between  4,000,000 
and  5,000,000  per  cubic  millimeter  in  the  case  of  average  se- 
verity, the  minimum  count  being  reached  at  about  the  time  of 
the  decline  of  the  temperature  ;  but  in  complicated  cases  the 
anemia  is  more  marked,  and  histological  degenerative  changes 
of  the  corpuscles  have  been  noted  during  the  period  of  desqua- 
mation. Van  den  Berg's  examinations  of  12  cases  ^  show  that 
the  count  is  usually  above  4,000,000  per  cubic  millimeter,  except 
in  severe  cases  complicated  by  acute  nephritis,  or  endocarditis, 
in  the  event  of  which  a  rapid  and  striking  anemia  is  produced, 
the  hemoglobin  sometimes  being  as  low  as  25  per  cent.,  and  the 
corpuscles  diminishing  to  as  low  as  2,000,000  per  cubic  milli- 
meter. From  an  analysis  of  the  cases  reported  by  Zappert,^ 
Felsenthal,^  Widowitz,^  and  others,  the  average  loss  of  erythro- 
cytes in  all  cases  amounts  to  about  1,000,000  cells  to  the  cubic 
millimeter,  but  Kochetkoff^  notes  a  more  decided  average  reduc- 
tion, this  author  stating  that  they  progressively  decrease  to  about 
3,000,000,  and  that  regeneration  is  slow  and  gradual,  not  being 
completed  for  a  period  of  six  weeks. 

A  well-marked  leucocytosis,  the  count  usually 
Leucocytes,  ranging  between  20,000  and  30,000  per  cubic 
millimeter,  occurs  in  the  majority  of  cases,  often 
first  appearing  several  days  in  advance  of  the  cutaneous  eruption, 
and  persisting  in  some  cases  long  after  convalescence  has  been 
established.  Its  duration  varies  widely  in  different  instances  ;  in 
some  cases,  not  necessarily  of  a  severe  type,  the  leucocytosis 
persists  for  ten,  or  even  thirty  days  ;  while  in  others,  usually  of  a 
mild  type,  it  disappears  before  the  temperature  has  fallen  to 
normal.  The  maximum  degree  of  increase  is  reached  from  four 
to  six  days  after  the  onset  of  the  illness. 

In  asthenic  cases  the  number  of  leucocytes  is  increased  but 
slightly,  or  not  at  all ;  but  in  the  well-nourished  child,  the  degree 
of  leucocytosis  may  be  regarded  as  a  rough  gauge  of  the  intensity 
of  the  infection,  being  usually  greater  in  severe  than  in  mild  cases. 
The  increase  appears  to  bear  no  fixed  relationship  either  to  the 
anginal  infection,  or  to  the  glandular  involvement,  for  marked  leu- 
cocytosis has  been  observed  in  cases  with  mild  angina,  unac- 
companied by  swelling  of  the  glands.  Neither  can  any  clear  re- 
lation be  established  between  the  leucocytosis  and  the  character 

1  Loc.  cit. 

2Zeitschr.f.  klin.  Med.,  1893,  vol.  xiii.,  p.  292. 

3Archiv.  f.  Kinderheilk.,  1892-3,  vol.  xv.,  p.  82. 

*  Loc.  cit. 

5  Vrach,  1891,  vol.  xii.,  p.  919. 


426  GENERAL    HEMATOLOGY. 

of  the  temperature,  the  period  of  desquamation,  and  the  inflam- 
matory complications  of  the  ear  and  kidney. 

In  all  of  van  den  Berg's  cases  the  number  of  leucocytes  was 
in  excess  of  normal,  the  "first  counts"  averaging  slightly  more 
than  17,000  per  cubic  millimeter,  and  the  leucocytosis  being 
higher  than  30,000  in  only  2  cases.  The  investigations  of  the 
other  authors  above  referred  to  give  practically  the  same  results, 
although  somewhat  higher  counts  have  been  made  in  some  in- 
stances. Mackie  ^  found  leucocytosis  constant  in  25  cases,  and 
in  one  patient  with  severe  anginal  symptoms  the  count  rose  to 
93,300.  He  failed  to  observe  any  signs  of  a  leucocyte  increase 
until  twenty-four  hours  after  the  appearance  of  the  rash. 

The  leucocytosis  is  generally  due  to  an  increase  in  the  poly- 
nuclcar  iiLiitt'ophiles,  these  cells  ranging  from  85  to  90  per  cent.; 
but  in  some  instances  the  increase  is  more  evenly  divided  between 
the  polymorphous  and  mononuclear  forms,  so  that  from  70  to 
80  per  cent,  of  the  former  and  from  1 5  to  30  per  cent,  of  the 
latter  may  be  found.  The  writer  has  noticed  the  presence  of 
large  numbers  of  the  so-called  transitio7ial  mononuclear  leu- 
cocytes, and  of  an  occasional  myelocyte.  Van  den  Berg  has 
noted  the  presence  of  small  numbers  of  myelocytes  in  grave 
cases.  Contrary  to  the  rule  which  holds  good  in  most  febrile 
conditions,  the  number  of  cosinopJiiles  in  favorable  cases  of  scarlet 
fever  remains  normal,  or,  indeed,  may  be  decidedly  increased. 
In  very  grave  cases  a  decrease  or  absence  of  these  cells  is  usually 
found.  In  cases  with  nephritic  complications  their  increase  is 
thought  to  be  favorable.  The  proportion  of  eosinophiles  is  us- 
ually from  4  to  5  per  cent,  of  the  other  forms,  sometimes  even 
10  or  15  per  cent.,  especially  during  the  post- febrile  period  of 
the  disease. 

The  blood  plaques  are  normal  at  the  beginning  of  the  attack, 
but  a  large  increase  in  the  number  of  these  elements  is  said  to 
occur  during  the  period  of  desquamation. 

The  presence  of  leucocytosis  and  persistence 

Diagnosis.      of  the  eosinophiles,  are  suggestive  signs  in  distin- 
guishing scarlet  fever  from  measles,  since  in  un- 
complicated cases  of  the  latter  disease  these  changes  are  absent. 
Disappearance  of  the  eosinophiles  is  regarded  as  a  bad  prognos- 
tic sign. 

1  Lancet,  1901,  vol.  ii.,  p.  525. 


SEPTICEMIA    AND    PYEMIA.  427 


LVII.     SEPTICEMIA    AND   PYEMIA. 

The  blood  changes  found  in  those  conditions 
General       due  to  the  presence  in  the  circulating  blood  of 

Features.  septic  bacteria  or  their  toxines,  geyieral  septicetnia, 
sapremia,  and  pyemia,  are  similar,  and  therefore 
may  be  considered  together  under  the  above  heading.  An  ap- 
parently trivial  infected  wound  may  give  rise  to  just  as  severe 
blood  changes  as  an  intense  pyemia  with  widespread  metastatic 
abscesses,  since  these  alterations  depend  rather  upon  the  virulence 
of  the  infection  and  the  reaction  which  it  provokes,  than  upon  the 
character  of  the  exciting  lesion  and  the  specific  nature  of  the 
offending  organisms.  Clinically,  these  blood  changes  may  be 
associated  with  such  conditions  as  infected  wounds,  osteomyelitis, 
malignant  endocarditis,  puerperal  fever,  septic  joints,  and  many 
other  lesions  for  which  various  septic  micro-organisms  are  held 
responsible. 

The  amount  of  fibrin  is  often  appreciably  increased  in  cases  in 
which  the  reaction  against  the  infection  is  well  marked,  especially 
in  the  early  stages  of  the  illness.  A  decrease  in  fibrin  is,  how- 
ever, common  in  patients  with  pronounced  anemia,  and  in  those 
who  readily  succumb  without  reaction  against  the  infection. 

Thus  far,  the  serum  test  has  given  no  reliable  clinical  informa- 
tion in  this  class  of  diseases,  although  several  clinicians  of  the 
French  school  claim  occasionally  to  have  observed  typical  clump- 
ing of  streptococcus  bouillon  cultures  with  the  serum  of  patients 
suffering  from  streptococcus  infections,  such  as  streptococcus  in- 
fected wounds,  sepsis,  puerperal  fever,  and  erysipelas  ;  but  nega- 
tive results  were  obtained  in  testing  bouillon  cultures  of  the 
staphylococcus  with  the  serum  of  staphylococcus  septicemia. 
The  evidence  brought  forward  to  show  that  the  serum  of 
patients  suffering  from  colon  infections  clumps  cultures  of  the 
colon  bacillus,  is  by  no  means  conclusive ;  for  many  races  of  the 
colon  bacillus,  it  may  be  recalled,  clump  spontaneously,  and  are 
agglutinated  by  normal  serum.  If  a  test-tube  containing  blood 
serum  of  a  patient  suffering  from  pneumococcus  septicemia  is 
inoculated  with  a  pure  culture  of  the  pneumococcus,  it  will  be 
found  that,  after  twenty-four  hours'  incubation,  the  serum  still 
remains  free  from  turbidity,  and  shows  simply  a  slight  sediment 
composed  of  pneumococci,  capsuleless  and  glued  together  in 
tenacious  clumps,  or  in  serpentine,  trailing  designs.  Pneumococci 
grown  in  normal  serum  cloud  the  liquid,  and  develop  a  new 
growth  consisting  of  encapsulated,  isolated  organisms.     Favorable 


428  GENERAL    HEMATOLOGY. 

results  have  been  reported  by  several  Continental  writers  who 
have  used  this  test  clinically,  but  its  diagnostic  value  must  still  be 
regarded  as  questionable. 

In  the  great  majority  of  cases  of  septicemia 
Bacteriology,  and  pyemia,  cultures  from  the  blood  prove  ster- 
ile, but  such  negative  results  neither  exclude  the 
existence  of  a  septic  process,  nor  necessarily  indicate  a  favorable 
prognosis.  On  the  other  hand,  positive  results  are  often  of  the 
greatest  value  in  the  diagnosis  of  obscure  cases  of  sepsis,  in 
which  the  clinical  manifestations  are  more  or  less  vague.  As 
pointed  out  by  Welch, ^  blood  cultures  in  which  the  staphylococ- 
cus pyogenes  albus  is  demonstrated  have  little  significance  in  the 
prognosis  of  the  case,  whereas  the  presence  in  the  blood  of  the 
other  pyogenic  cocci  is  almost  invariably  a  grav^e  sign. 

The  results  obtained  by  different  investigators  in  the  bacterio- 
logical examination  of  the  blood  in  septicemia  vary  within  wide 
limits,  these  variations  being  explained  partly  by  the  differences 
in  the  technical  methods  used  by  each  reporter,  and  partly  per- 
haps by  the  nature  of  the  infection.  Petruschky  -  obtained  17 
positive  results  in  the  examination  of  59  cases  of  sepsis,  strepto- 
cocci being  found  in  15,  and  staphylococci  in  2  instances.  Sitt- 
man  ^  examined  53  cases  of  septicemia,  and  succeeded  in  iso- 
lating streptococci  in  4,  staphylococci  in  1 1,  and  pneumococci  in 
6.  Czerniewski  ^  in  37  cases  of  puerperal  sepsis  obtained  posi- 
tive results  in  10,  pure  cultures  of  streptococci  being  found  in  all 
the  grave  infections.  Symes^  obtained  positive  cultures  in  9  out 
of  3  I  cases  of  sepsis,  the  staphylococcus,  the  streptococcus,  the 
pneumococcus,  and  the  micrococcus  tetragenus  having  been  the 
organisms  identified.  Kiihnau's  investigations^  show  a  much 
lower  percentage  of  positiv^e  findings  than  are  commonly  re- 
ported, for  this  author  in  23  cases  of  septico-pyemia  obtained 
growths  in  only  3  instances,  while  but  a  single  positive  finding 
resulted  from  the  examination  of  12  cases  of  ulcerative  endo- 
carditis. Krauss,^  who  has  had  a  very  large  experience  in  the 
bacteriological  investigation  of  the  blood  in  various  infectious 
diseases,  reports  7  positive  results  in  a  series  of  22  cases  of  sep- 
ticemia,  ulcerative  endocarditis,  and    erysipelas.     White  ^  in    18 

1  Dennis'  "System  of  Surgery,"  Phila.,  1S95,  vol.  i.,  p.  251. 

^Zeitschr.  f.  Hygiene,  1894,  vol.  xvii.,  p.   59. 

3Deut.  Archiv.  f.  klin.  Med.,  1894,  vol.   liii.,  p.  323. 

*  Archiv.  f.  Gynaekol.,  1888,  vol.  xx^iii.,  p.  73. 

5  British  Med.  Journ.,  1 901,  vol.  ii.,  p.  709. 

^Zeitschr.  f.  Hygiene,  1897,  '^^^-  xxv.,  p.  492. 

"  Zeitschr.  f.  Heilk.,  1896,  vol.  xvii.,  p.  117. 

s Journ.  of  Exper.  Med.,  1899,  vol.  iv.,  p.  425. 


SEPTICEMIA    AND    PYEMIA.  429 

severe  cases  of  sepsis,  all  of  which  were  fatal,  obtained  positive 
findings  in  4 ;  the  streptococcus  pyogenes  3  times,  and  the 
staphylococcus  pyogenes  aureus  once.  Canon  ^  obtained  11 
positive  results  in  the  examination  of  17  cases  of  septicemia, 
pyemia,  and  osteomyelitis.  Hirschlaff"  obtained  the  streptococcus 
or  staphylococcus  7  times,  in  cultures  made  from  8  cases  of 
sepsis.  James  and  Tuttle  ^  in  6  severe  septic  infections  suc- 
ceeded in  finding  the  streptococcus  in  2  instances.  Brieger  ^ 
obtained  uniformly  negative  findings  in  the  examination  of  6 
cases  of  puerperal  sepsis.  Similar  results  have  also  been  re- 
ported by  Neumann  ^  who  obtained  negative  findings  in  blood 
cultures  from  5  cases  of  pyemia.  Grawitz^  cultured  pyogenic 
cocci  only  once  in  his  examination  of  7  cases  of  malignant  en- 
docarditis. 

Consideration  of  these  figures,  together  with  the  statistics  of  a 
number  of  other  reporters  of  smaller  series  of  cases,  furnishes  a 
total  of  316  cases  of  sepsis  in  which  it  is  reasonable  to  presume 
that  the  bacteriological  examination  of  the  blood  has  been  made 
by  dependable  methods.  Of  these  316  cases,  positive  results 
were  obtained  in  107,  while  the  remaining  209  proved  negative — a 
percentage  of  33.8  for  the  former.  This  analysis,  however,  is  not 
to  be  regarded  as  equivalent  to  the  statement  that  bacteriological 
examination  of  the  blood  gives  positive  diagnostic  information  in 
one-third  of  all  cases,  for  the  results  of  a  single  reHable  observer, 
rather  than  the  aggregate  figures  of  several,  are  to  be  considered 
in  order  to  arrive  at  a  true  estimate  of  the  value  of  this  procedure. 
The  writer  is  inclined  to  believe  that  White's  results  accurately 
express  the  value  of  blood  cultures  in  this  class  of  infections. 

Anemia,  of  a  grade  proportionate  to  the  inten- 
Hemoglobin    sity  of  the  infection,  is  the  rule  in  septic  cases, 
AND  regardless  of  the  specific  nature  of  the  infective 

Erythrocytes,  process.  In  very  acute  cases  the  diminution  ot 
hemoglobin  and  erythrocytes  may  be  so  excessive 
and  so  rapid  that  an  abrupt  downward  curve  in  the  erythrocyte 
line  of  the  blood  chart  may  be  detected  from  day  to  day,  even 
from  morning  until  night,  in  some  instances.  This  rapidly  de- 
veloping type  of  anemia  is  associated  especially  with  fialminant 
cases  of  puerperal  septicemia,  in  which  counts  of  less  than  1,000,- 
000  cells  per  cubic  millimeter  have  been  frequently  reported. 

^  Deut.  Zeitschr.  f.  Chirurg.,  1893,  ^°^-  xxxvii,,  p.  571. 

2  Deut.  med.  Woch.,  1897,  vol.  xxiii.,  p.  766. 

'^Loc.  cit. 

*Charite-Annal.,  1888,  vol.  xiii.,  p.  198. 

5  Bed,  klin.  Woch.,  1888,  vol.  xxv.,  p.  143. 

s  Charite-Annal. ,  1894,  vol.  xix,,  p.  154. 


43 O  GENERAL    HEMATOLOGY. 

In  less  severe  cases  the  development  of  the  anemia  is  slower 
and  of  a  more  moderate  grade,  the  hemoglobin  being  reduced  to 
40  or  50  per  cent.,  and  the  erythrocytes  to  from  about  2,500,000 
to  3,500,000  per  cubic  millimeter. 

The  following  estimates  show  the  blood  changes  found  in  a 
case  of  puerperal  sepsis  during  a  period  of  four  months  : 


Hemoglobin 

Erythrocytes 

Leucocytes 

Date. 

Percentage. 

PER    CB.   MM. 

PER  CB.  MM. 

4-29-01. 

57 

3,380,000 

17,200 

5-16-OI. 

52 

3,390,000 

14,200 

6—  2-01. 

38 

2,640,000 

29,400 

6-  9-01. 

22 

2,000,000 

33.100 

6-12-01. 

25 

1,600,000 

19,000 

6-1 6-0 I. 

30 

1,850,000 

16,800 

6-21-0 I. 

25 

1,902,250 

27,200 

6-27-01. 

35 

2,339>ooo 

19,200 

7-  5-0  T. 

30 

2,050,000 

8,600 

7-22-01. 

30 

2,300,000 

6,000 

8-  6-01. 

35 

3,150,000 

15,000 

8-1 5-0 1. 

39 

3,787,000 

10,500 

8-22-01." 

48 

3,637,000 

9,200 

8-25-01. 

52 

3,899,000 

9,000 

In  twenty-one  hospital  cases  of  septicemia  and  pyemia  the  hem- 
oglobin and  erythrocyte  values  were  as  follows  : 

Erythrocytes.  Cases. 

Above  5,000,000  I 

From    4,000,000  to  5,000,000  3 

"       3,000,000  to  4,000,000  8 

"       2,000,000  to  3,000,000  7 

"       1,000,000  to  2,000,000  2 

Average:    3,150,490  per  cb.  mm. 
Highest:    5,390,000    "     "      " 
Lowest:     1,093,000    **     *'       " 

The  color  index  is  usually  quite  low,  for  the  hemoglobin  loss 
is  as  a  rule  relatively  greater  than  the  corpuscular  decrease ;  it 
averaged  0.67  for  this  series.  Hemoglobinemia  may  be  recognized 
in  occasional  instances  of  grave  character.  Most  writers  lay  stress 
on  the  excessively  watery  condition  of  the  serum,  particularly  in 
those  cases  in  which  the  development  of  anemia  is  early,  marked, 
and  rapid. 

Deformities  of  shape  and  size  and  atypical  staining  phenomena 
are  marked  in  relation  to  the  degree  of  the  anemia  ;   they  are 


Hemoglobin. 

Cases. 

From  60  to  70  per 

cent. 

2 

''     50  to  60    '' 

( ( 

3 

''     40  to  50    " 

i( 

8 

"     30  to  40    " 

(I 

3 

*'     20  to  30    " 

(  c 

4 

Below  20              '' 

11 

I 

Average :   42.4  per 

cent. 

Highest:    64        '' 

<( 

Lowest :     19        *  * 

( ( 

SEPTICEMIA    AND    PYEMIA.  43  I 

rarely  conspicuous,  except  in  long-standing  cases.  The  same  re- 
marks apply  to  the  presence  of  nucleated  erythrocytes.  Granular 
basophilia  is  found  with  more  or  less  constancy,  in  severe  cases. 
Leucocytosis  is  always  present  in  those  cases 

Leucocytes,  in  which  the  infection,  either  moderate  or  marked, 
occurs  in  a  patient  whose  powers  of  resistance  are 
sufficiently  strong  to  react  against  the  poison.  The  increase  in 
the  number  of  leucocytes  is  usually  moderate — from  about  1 5,000 
to  25,000  in  the  average  case.  In  trifling  infections,  not  suf- 
ficiently marked  to  produce  activity  of  the  leucocyte-forming 
organs,  and  in  lethal  cases,  in  which  the  system  is  overwhelmed 
by  the  toxines,  not  only  does  leucocytosis  fail  to  develop,  but  in 
some  instances  distinct  leucopenia  may  be  observed.  These  facts 
render  the  occurrence  of  leucocytosis  in  septicemia  an  extremely 
inconstant  sign,  for  it  is  no  uncommon  experience  to  examine  case 
after  case  of  undoubted  sepsis,  without  encountering  any  increase 
in  the  leucocytes  above  normal.  Thus,  in  the  above  series 
frank  leucocytosis  was  found  in  only  12  instances,  or  but  a  trifle 
more  than  55  per  cent,  while  in  4  cases,  or  nearly  20  per  cent., 
there  was  distinct  leucopenia,  the  court  in  one  being  only  2,000 
per  cubic  millimeter.  All  the  cases  not  showing  leucocytosis 
were  either  very  mild  or  very  severe  infections. 

In  tabular  form  these  cases  may  be  summarized  as  follows  : 

Above 
From 


20,000 

m 

2 

cases. 

15,000-20,000 

a 

5 

(( 

10,000-15,000 

(( 

5 

(I 

5,000—10,000 

1 1 

5 

i  ( 

5,000 

ei 

4 

(I 

Below 

Average  of  21  cases:    13,852  per  cb.  mm. 

*'         "  12      "     with  leucocytosis :    18,793  per  cb.  ^^''* 
Highest:    41,600  per  cb.  mm. 
Lowest :        2,000  per  cb.  mm. 

The  increase  affects  chiefly  the  polynudear  neutropJiiles ,  which 
are  both  relatively  and  absolutely  increased  at  the  expense  of  the 
mononuclear  forms.  In  a  profoundly  anemic  case  of  sepsis  Kline  ^ 
found  striking  eosinophilia — 40  per  cent.  In  all  forms  of  sepsis, 
and  especially  in  puerperal  fever,  the  iodine  reaction  occurs  with 
great  constancy. 

The  value  of  the  blood  examination  as  an  aid  to 

Diagnosis,      the  diagnosis  of  septic  conditions  must  be  regarded 

as  more  or  less  uncertain.     In  cases  with  clinical 

manifestations  suggesting   at    once  enteric  fever,  malarial  fever, 

and  septicemia,  the  presence  of  leucocytosis  is  highly  suggestive 

^Centralbl.  f.  inn.  Med.,  1899,  vol.  xx.,  p.  97. 


432  GENERAL    HEMATOLOGY. 

of  the  latter  condition,  for  in  typhoid  and  in  malaria  leucocytosis 
rarely  exists,  except  in  the  event  of  some  complication.  The 
early  development  of  a  rapidly  increasing  anemia  would  also  point 
to  sepsis  rather  than  to  typhoid  or  malaria,  for  in  the  latter  fevers 
the  anemia,  although  it  begins  early,  does  not  reach  a  high  grade 
until  comparatively  late  in  the  course  of  the  illness.  The  pres- 
ence of  a  positive  serum  reaction,  or  the  discovery  of  malarial 
parasites  in  the  blood  will,  of  course,  at  once  determine  the 
diagnosis.  If  the  diagnosis  lies  between  sepsis  and  miliary  tuber- 
culosis, increase  in  the  number  of  leucocytes  points  to  the  former. 
In  cases  without  leucocytosis,  and  these,  unfortunately,  are  most 
common,  the  results  of  the  blood  examination  are  necessarily 
valueless,  unless  positive  bacteriological  findings  should  be  ob- 
tained. The  latter,  after  all,  are  the  only  absolutely  dependable 
signs  to  be  obtained  from  the  study  of  the  blood  in  this  class 
of  cases. 

LVIII.     SYPHILIS. 

During  the  early  stages  of  the  infection,  in  the 
Hemoglobin    interval    between    the   appearance    of  the  initial 
AND  lesion  and  the  development  of  secondary  symp- 

Erythrocytes.  toms,  the  blood  changes  closely  counterfeit  those 
of  typical  chlorosis,  a  fact  which  has  led  to  the 
use  of  the  term  "syphilitic  chlorosis,"  to  describe  the  blood- 
picture  of  early  lues.  The  hemoglobin  progressively  falls  until 
the  loss  approximates  twenty  or  thirty  per  cent.,  while  the  num- 
ber of  erythrocytes  remains  normal,  or  is  but  slightly  diminished, 
in  consequence  of  which  the  color  index  is  low.  As  secondary 
symptoms  appear,  oligocythemia  usually  develops,  and  in  some 
instances  reaches  a  high  grade.  There  is  a  close  relationship 
between  the  intensity  of  the  infection  and  the  intensity  of  the 
anemia.  In  the  tertiary  and  hereditary  forms  of  the  disease  the 
counfmay  fall  to  approximately  one  million  cells,  and  the  hemo- 
globin to  twenty  per  cent,  or  even  less,  while  extreme  poikilo- 
cytosis,  megalocytosis,  and  microcytosis  may  be  present,  together 
with  numerous  normoblasts  and,  perhaps,  a  few  megaloblasts — 
the  so-called  "  syphilitic  pernicious  anemia." 

After  the  administration  of  mercuiy  both  the  hemoglobin  and 
erythrocytes  begin  to  increase,  the  former  more  slowly  than  the 
latter,  until  treatment  has  been  continued  for  about  two  or  three 
weeks,  but  should  this  drug  be  given  for  longer  than  this 
period,  just  the  opposite  effect  is  produced,  first  a  diminution 
in  the  hemoglobin  percentage,  followed  later  by  oligocythemia. 
Extreme  hemoglobin  loss  under  such  a  circumstance  is  regarded 


SYPHILIS.  433 

as  prognostic  of  severe  tertiary  manifestations,  as  the  infection 
matures.  The  intravenous  injection  of  mercuric  chloride  rapidly 
causes  hemoglobinemia  in  syphilitics.  It  is  a  well-recognized 
clinical  fact  that  the  blood  changes  provoked  by  syphilis  are  likely 
to  be  more  marked  in  women  than  in  men,  other  things  being 
equal. 

Justus'    Test.     This   reaction,    described    by   Justus,^  depends 
upon    the    presumption    that  in   untreated    cases   of  congenital, 
secondary,  and  tertiary  syphilis,  a  single   dose  of  mercury,  ad- 
ministered either  by  inunction,  or  by  subcutaneous  or  intravenous 
injection,   causes  a  hemoglobin  loss  of  from  ten  to  twenty  per 
cent,  within  about  twenty-four  hours,  this  abrupt  decline  being 
followed  within  a  few  days  by  a  rise  in  the  hemoglobin  value  to 
a  somewhat   higher   figure  than  that  first  observed,  before  the 
drug  was  given.     Justus  obtained  uniformly  positive  results  in 
more  than  300  cases  of  syphilis,  and  negative  results  in  a  large 
number  of  non-syphilitic  control  cases.     Cabot  and  Mertins  ^  ob- 
tained positive  results  in  7  syphilitics,  and  also  in  one  case  of 
chlorosis  and  in  one  of  tertian  malarial  fever,  but  in  their  hands 
the  test  proved  negative  in  32  control  cases  of  other  diseases. 
Regarding  the  exceptional  non-syphilitic  diseases  in  which  the 
reaction  may  prove  positive,  Brown  and  Dale^  state  that  such 
cases  are  characterized    by  striking    oligochromemia.     A    thor- 
ough study  of  the  test  has  recently  been  made  by  Jones,*  who 
examined   53  cases,  of  which  number  35  were  syphilis,  and   18 
cases  of  other  diseases.     Of  the  former,  17  were  active  syphilis 
untreated,  and  of  these  the  test  was  positive  in  1 3  and  negative 
in  4 ;  fifteen  cases  of  chancre  yielded  but  7  positive  results,  these 
occurring  most  frequently  in  chancre  with  adenitis  ;  in  two  cases 
of  latent  syphilis  and  in  one  of  active  syphilis  under  treatment 
the  test  failed.      In  the  writer's  experience,  Hmited  to  9  cases,  the 
success  of  the  test  has  been  uniform. 

The  diagnostic  value  of  Justus'  test  is  greatly  restricted  by  its 
frequent  failure  in  early  initial  lesions  and  in  latent  syphilis,  and 
its  occasional  failure  in  the  early  part  of  the  secondary  stage, 
periods  when  a  pathognomonic  test  would  prove  of  the  greatest 
aid.  The  fact  that  positive  reactions  may  occur  in  non-syphilitic 
diseases  must  also  be  remembered. 

1  Verhandl.  d.  5.  Cong.  d.  Deut.  derraatol.  Gesellsch.,  Sep.,  1895.  Also  Virchow's 
Archiv.,  1894,  vol.  cxl.,  pp.  91  and  533. 

2  Boston  Med.  &  Surg.  Journ.,  1899,   vol.  cxl.,  p.  323. 

3  Cincinnati  Lancet-Clinic,  1900,  vol.  xliv.,  p.  261. 
*N.  Y.  Med.  Journ.,  1900,  vol.  Ixxi.,  p.  513. 


28 


434  GENERAL    HEMATOLOGY. 

The  number  of  leucocytes,  which  remains  ap- 
Leucocvtes.  proximately  normal  during  the  preeruptive  stage 
of  the  disease,  usually  increases  moderately  with 
the  appearance  of  the  secondary  symptoms.  Their  total  number 
rarely  equals  twice  the  maximum  normal  standard,  and  the  gain 
is  due,  in  the  great  majority  of  instances,  to  an  increase  in  the 
non-granular  Jiyaline  forms,  the  percentage  oi polymiclcar  ncntro- 
philes  being  relativel}'  low.  Many  authors  maintain  that  the 
cosinopJiilcs  are  increased,  but  Peter,^  who  has  especially  investi- 
gated this  question,  emphatically  states  that  in  no  form  and  at  no 
stage  of  syphilis  has  he  obsen-ed  eosinophilia.  In  the  leucocyte 
increase  frequently  found  in  the  high-grade  anemia  of  tertiary 
syphilis  the  lymphocytosis  is  especially  striking,  and  the  presence 
of  small  numbers  of  myelocytes  is  common.  Under  the  influence 
of  mercurial  or  iodide  treatment  the  leucocyte  count  diminishes, 
the  lymphocytes  decrease,  and  the  polynuclear  neutrophiles  grow 
more  numerous. 

But  sHght  diagnostic  value  can  be  attached  to 
Diagnosis,  the  changes  in  the  blood  in  this  disease.  The 
association  of  a  low  color  index  and  a  leucocyte 
increase  chiefly  of  the  lymphocytes,  is  suggestive,  but  nothing 
more.  Justus'  test,  if  positive,  strengthens  the  pertinence  of  the 
preceding  signs,  provided  that  all  sources  of  fallacy  can  be  ex- 
cluded ;  absence  of  the  reaction  by  no  means  excludes  syphilis. 
The  distinctions  between  tertiary  syphilitic  anemia  and  true  per- 
nicious anemia  have  already  been  discussed.     (See  page  230.) 

LIX.     TETANUS. 

In  a  single  fatal  case,  treated  with  antitoxin,  Cabot"  found  70 
per  cent,  of  hemoglobin  and  11,900  leucocytes  per  cubic  milli- 
meter, with  no  decrease  in  the  number  of  eosinophiles,  as  is 
usual  in  most  febrile  states. 

LX.     TONSILLITIS. 

As  a  general  rule,  no  appreciable  changes  are  found  in  the 
hemoglobin  and  erythrocytes^  although  in  severe  cases  the  former 
is  sometimes  diminished.  Leucocytosis  of  a  moderate  grade  may 
or  may  not  develop,  depending  largely  upon  the  character  of  the 
tonsillar  inflammation.  When  present  the  increase  involves  prin- 
cipally the  polynuclear  neutrophiles,  and  the  total  leucocyte  count 
rarely  exceeds  15,000  cells  to  the  cubic  milHmeter.     In  simple 

^  Derraatolog.  Zeitschr.,  1897,  ^o^-  i^'->  P-  669. 
2  Loc.  cit. 


TRICHINIASIS.  435 

catarrhal  tonsillitis  the  count  is  usually  normal,  but  leucocytosis  is 
common  in  follicular  tonsillitis  and  in  quinsy.  In  the  latter  Pee/ 
Rieder/  and  others  have  observed  leucocytosis  in  excess  of  20,000. 

LXI.     TRICHINIASIS. 

It  is  generally  agreed  that  there  are  no  changes 

Hemoglobin    in  the  hemoglobin  and  erythrocytes  attributable 

AND  to  the  influence  of  this  infection,  high  counts  and 

Erythrocytes,  hemoglobin  estimates,  often  polycythemia,  being 

the  rule.      Rarely,  well-marked  anemia  may  be 

found,  due  to  some  other  cause,  as  in  a  case  reported  by  Kerr,^  in 

which  the  erythrocytes  numbered  between  3,300,000  and  3,340,- 

000  per  cubic  miUimeter. 

T.  R.  Brown  ^  first  made  the  important  announce- 
Leucocytes.    ment  that  acute  cases  of  trichiniasis  are  accom- 
panied by  a  well-marked  increase  in  the  number 
of  leucocytes,  characterized  by  an  absolute  and  relative  gain  in 
the  eosinopJiiles,     This  observation  has  since  been  corroborated 
by  a  number  of  other  workers,  whose  results  are  tabulated  below. 
Unfortunately,  eosinophilia  can  not  be  regarded  as  constant  in 
this  condition,  as  shown  by  the  following  count  made  by  the  writer 
in  a  typical  case  of  trichiniasis  occurring  in  J.  Chalmers  DaCosta's 
surgical  service  at  St.  Joseph's  Hospital  : 

Hemoglobin,   80  per  cent. 

Erythrocytes,  4,400,000  per  cb.  mm. 

Leucocytes,            12,000    '*    *^  '' 

Small  lymphocytes 36.7  per  cent. 

Large  lymphocytes  and  transitional  forms  6. 5 

Polynuclear  neutrophiles 56.  i 

Eosi  nophiles 0.5 

Myelocytes 0.2 

Basophiles  0.0 

Repeated  examinations  by  others  showed  practically  these 
figures,  the  eosinophiles  at  no  time  being  increased.  The  lesions 
in  this  patient  were  most  striking,  as  they  involved  the  greater 
part  of  the  right  lower  extremity,  from  calf  to  thigh.  Excised 
bits  of  muscles  from  the  affected  parts  were  found  to  be  swarm- 
ing with  trichinae,  and  rich  in  eosinophile  cells.     It  is  possible 

^  Inaug.  Dissert.,  Berlin,  1890. 
2  Loc.  cit. 

sPhila.  Med.  Journ.,  1900,  vol.  vi.,  p.  346. 

*  Johns  Hopkins  Hosp.  Bull.,  1897,  vol.  iii.,  p.  79.  Also,  Journ.  of  Exper.  Med., 
1898,  vol.  iii.,  p.  315. 


436  GENEEIAL    HEMATOLOGY. 

that  in  such  instances  as  this,  the  absence  of  eosinophilia  may  be 
attributed  to  the  overwhelming  nature  of  the  toxines,  which,  by 
their  repellant  action,  stifle  eosinophile  proHferation  in  the  marrow. 
Howard  *  also  failed  to  find  an  eosinophile  increase  in  a  single 
case,  although  large  numbers  of  these  cells  were  detected  in  the 
muscle  lesions.  The  report  of  the  blood  examination  in  Howard's 
case  is  so  meagre  ("  Coverslip  preparations  of  the  blood  stained 
with  Ehrlich's  triacid  stain  on  examination  showed  a  slight  leuco- 
cytosis  but  no  increase  in  the  number  of  the  eosinophilic  cells") 
that  it  must  be  omitted  from  the  following  list  of  18  cases  reported 
since  1897. 


,        ,  ^  Total  Number  of  Leuco-    ^  ^.^'^"J.f  Percentage  of 

Name  of  Reporter.       !      No.  of  Cases.  cvtes  per  cb.  mtn.        \  Eosinophiles  to  other  Forms 


T.  R.  Brown.  2 
Gwyn.'' 


of  Leucocytes. 


3  I        8,000-35,000  8-68.2 

I  17,000  '•  33-65-9 


Kerr.*  2  '       10,000-25,000  18.1-86.6 

Blumer  &  Neuman.5  9  ;        6,000-24.000  8-50.4 

Stump.6  ,.  I  I j  52 

Cabot.  7  I  7,000-11,000        ,  17-28 

Atkinson.  8  I 28,000 ' 35-58.5 

The  other  differential  changes,  which  are  unimportant,  consist 
in  a  corresponding  relative  decrease  in  the  polymiclcar  nt^ttro- 
philes,  and,  occasionally,  in  the  early  stages  of  some  cases,  in  a 
similar  diminution  in  the  lyvipJiocytcs.  Mast  cells,  in  the  propor- 
tions of  I  or  2  per  cent.,  have  also  been  obser\^ed,  although  not 
constantly. 

Blumer  and  Neuman's  studies  of  9  cases  of  epidemic  trichini- 
asis,^  lead  them  to  conclude  that  the  degree  of  leucocyte  increase 
corresponds  in  a  general  way  to  the  severity  of  the  attack,  rela- 
tively severe  cases  being  attended  with  a  higher  and  more  per- 
sistent increase  than  the  milder  attacks  ;  on  the  other  hand,  the 
intensity  of  the  infection  does  not  necessarily  correspond  to  the 
degree  of  eosinophilia.  The  latter  may  persist  for  months  after 
the  disappearance  of  the  leucocytosis  and  the  apparent  convales- 
cence of  the  patient,  but  just  how  long  it  does  last  is  as  yet  un- 
determined. 

1  Phila.  Med.  Journ.,  1899,  vol.  iv.,  p.  1085. 

2  Loc.  cit. 

'Centralbl.  f.  Bakt.  u.  Parasit.,  1899,  vol.  xxv.,  p.  746. 
*  Loc.  cit. 

5  Am.  Journ.  of  Med.  Sc,  1900,  vol.  cxix.,  p.  14. 

6  Phila.  Med.  Journ.,  1899,  vol.  iii.,  p.  1318. 

'Boston  Med.  and  Surg.  Journ.,  1897,  vol.  cxxxvii.,  p.  676. 
8 Phila.  Med.  Journ.,  1899,  vol.  iii.,  p.  1243. 
9  Loc.  cit. 


TUBERCULOSIS.  43/ 

The  presence  of  an  eosinophile  leucocytosis, 
Diagnosis,  usually  of  a  high  grade,  may  be  the  only  indica- 
tion of  trichiniasis  in  obscure  cases  in  which  the 
characteristic  symptoms  of  the  infection  are  wanting,  and  in  such 
instances  the  change  is  to  be  regarded  as  a  most  valuable  aid  to 
diagnosis.  Absence  of  this  sign,  however,  does  not  definitely  ex- 
clude the  disease. 

LXII.    TUBERCULOSIS. 

A  pure  infection  with  Koch's  bacillus  of  tuber- 
General       culosis   is   capable   of  producing    comparatively 
Features,      slight  alteration  in  the  composition  of  the  blood, 
such  changes  as  may  be  associated  with  tuber- 
culous processes,  whatever  organs  they  involve,  being  due  chiefly 
to  secondary  infection  with  other  bacteria,  usually  of  pyogenic 
type,  and  not  to  the  disease,  per  se.     The  prolonged  ill  effects  of 
tuberculosis  upon  bodily  nutrition  must  also  in  time  cause  more 
or  less  blood  impoverishment,  but  it  is  a  well-recognized  clinical 
fact  that  the  changes  are  as  a  rule  trivial  in  comparison  with  the 
gravity  of  the  disease,  and  the  apparent  degree  of  cachexia.    The 
above   facts  are  sufficient  to  explain  the  reason  for  the  varied 
blood-pictures  found  in  tuberculosis — pictures  ranging  from  those 
of  practically  normal  blood  to  those  of  most  intense  anemia,  and 
from  leucopenia  to  frank  leucocytosis. 

In  a  limited  number  of  cases  of  acute  miliary 
Bacteriology,  tuberculosis  the  specific  bacillus  has  been  isolated 
from  the  blood  during  life  by  culturing,  but  in 
this,  as  well  as  in  the  other  forms  of  the  disease,  this  procedure 
generally  results  negatively  so  far  as  the  detection  of  the  tubercle 
bacillus  is  concerned.  In  advanced  septic  cases  of  pulmonary 
tuberculosis,  streptococci,  staphylococci,  and  other  micro-organ- 
isms have  been  found  in  the  blood,  but  only  rarely,  for  the  septic 
process  tends  to  remain  localized  in  the  lungs,  rather  than  to  in- 
vade the  general  circulation. 

Serum  Test.  Arloing  and  Courmont  ^  have  succeeded  in  pre- 
paring cultures  with  which  they  claim  that  the  serum  diagnosis 
of  tuberculosis  can  be  carried  out.  Glycerine  peptone  bouil- 
lon inoculated  with  an  old,  attenuated  culture  of  the  tubercle 
bacillus  and  thoroughly  agitated  each  day  to  insure  homoge- 
neity of  the  culture,  finally  develops  a  growth  in  which  the 
bacilli  are  uniformly  disseminated  and  actively  motile.  Blood 
serum  from  the  suspected  case  is  mixed  in  small  test-tubes 
with  the    culture    thus    prepared,  in   proportions  of   i    to    5,    i 

1  Congres  pour  1' Etude  de  la  Tuberculose,  1898. 


43 8  GENERAL    HEMATOLOGY. 

to  ID,  and  I  to  20,  and  the  tubes  inclined  at  an  angle  of  forty- 
five  degrees,  being  examined  at  intervals  of  two,  ten,  and 
twent}^-four  hours.  A  positive  reaction  is  indicated  by  a  clarifica- 
tion of  the  mixture  and  the  deposition  of  small  flakes  or  granules 
in  the  bottom  of  the  tube,  while  microscopically  it  may  be  seen 
that  the  bacilli  are  clumped  and  motionless.  Reactions  occurring 
after  the  lapse  of  twenty-four  hours  are  without  cHnical  signifi- 
cance. With  normal  serum  in  a  dilution  of  I  to  5  positive  re- 
actions do  not  occur,  and  they  occur  but  rarely  with  tuberculous 
serum  in  a  dilution  higher  than  i  to  20.  A  peculiarity  about 
this  test  is  that  it  takes  place  in  an  inverse  ratio  to  the  intensit}^ 
of  the  infection,  and  hence  fails  in  advanced  and  virulent  cases  in 
which  presumably  there  is  alread}^  an  excessive  auto -intoxication 
with  tuberculin.  Excluding  such  cases,  Arloing  and  Courmont 
found  that  positive  reactions  were  constant  in  all  tuberculous 
patients,  but,  unfortunately,  they  also  found  similar  results  in 
some  normal  individuals  and  in  various  non-tuberculous  diseases. 
Bendix  ^  found  the  test  successful  in  34  of  36  cases  of  tubercu- 
losis, the  2  failures  being  in  instances  of  overwhelming  infections  ; 
he  also  claims  that  normal  blood  and  the  blood  from  other  dis- 
eases gives  negative  results.  Nine  cases  of  pulmonaiy  tubercu- 
losis, 4  of  pleurisy,  and  17  of  various  non-tuberculous  affections 
were  examined  by  Mongour  and  Buard.-  All  the  phthisis  cases, 
and  3  of  the  4  pleurisies,  which  were  tuberculous,  were  positive, 
the  case  not  reacting  proving  to  be  non-tuberculous.  In  1 5  of  17 
other  diseases,  the  results  of  the  test  corresponded  with  the 
clinical  diagnosis  and  the  autops}-  findings.  Similar  results  in 
tuberculous  pleurisy  were  obtained  by  P.  Courmont,^  who  found 
positive  reactions  in  10  of  11  cases  clinically  tuberculous,  while 
of  9  cases  clinically  non-tuberculous,  4  w^ere  positive  and  5  nega- 
tive. In  1 2  cases  of  ascites,  7  due  to  hepatic  cirrhosis  failed  to 
react,  but  the  other  5,  all  clinically  tuberculous,  gave  positive  re- 
sults. Results  distinctly  less  favorable  than  those  reported  by 
other  investigators  are  published  by  Beck  and  Rabinowitch,^  but 
it  is  not  at  all  improbable  that  these  discrepancies  may  be  attrib- 
uted, at  least  in  part,  to  the  use  of  unsuitable  cultures.  Ac- 
cording to  these  authors'  experiments,  only  6  of  17  cases  of  in- 
cipient lung  tuberculosis  were  positive,  and  but  4  of  16  advanced 
cases.     Of  5  suspected  cases  that  reacted  to  tuberculin  injections, 

^  Deut.  med.  Woch.,  1900,  vol.  xxvi.,  p.  224. 

^Compt   rend.  Soc.  bioL,  Paris,  1898,  10  s.,  vol.  v.,  p.  1142.     Also,  Buard:  Journ. 
de  pliys.  el  path,  gen.,  1900,  vol.  ii.,  p.  797. 

■■' (."ongres  pour  1' Etude  de  la  Tuberculose,  189S. 
*  Deut.  med.  Woch.,  1900,  vol.  xxvi.,  p.  400. 


TUBERCULOSIS.  439 

but  a  single  one  gave  a  positive  serum  reaction.  They  further- 
more found  that  positive  reactions  may  occur  in  healthy  persons, 
and  in  rheumatic  fever,  bronchitis,  hepatic  cirrhosis,  and  croupous 
pneumonia.  Romberg  ^  has  determined  that  the  serum  of  more 
than  50  per  cent,  of  persons  who  fail  to  show  clinical  evidences 
of  tuberculosis  possesses  a  more  or  less  agglutinative  property. 

The  serum  reaction  in  tuberculosis,  as  at  present  elaborated, 
must  be  considered  of  questionable  diagnostic  value,  since  it  has 
been  shown  that  it  may  occur  in  normal  individuals  and  in  non- 
tuberculous  diseases,  and  that  it  may  often  be  negative  in  affec- 
tions undoubtedly  tuberculous.  As  compared  with  Widal's 
typhoid  reaction,  the  test  of  Arloing  and  Courmont  is  crude  and 
untrustworthy. 

The  change  most  frequently  observed  is  a  mod- 
Hemoglobin    erate  loss  of  hemoglobin,  with  little  or  no  decrease 
AND  in  the  number  of  erythrocytes,  and  a  low  color 

Erythrocytes,  index,  resembling  somewhat  the  blood-picture  of 
chlorosis.  In  such  instances  poorly  colored,  small 
sized  corpuscles  may  be  numerous,  but  poikilocytes  and  other 
structural  alterations  in  the  cells  are  absent.  In  cases  in  which 
the  effects  of  a  complicating  septicemic  process  are  active,  the 
above  changes  may  be  aggravated,  and  a  secondary  anemia  of 
variable  intensity  is  thus  developed.  The  oligocythemia  becomes 
marked  and  more  proportionate  to  the  oHgochromemia,  the  color 
index  consequently  rising;  deformities  of  shape  and  size,  and 
degenerative  stroma  changes  become  evident ;  and  in  severe  cases 
an  occasional  normoblast  may  stray  into  the  circulation,  especially 
after  the  occurrence  of  a  hemorrhage.  But  these  qualitative 
changes,  even  in  advanced  cases  with  marked  cachexia,  are  com- 
paratively uncommon,  and,  when  present,  are  usually  not  striking, 
in  spite  of  the  gravity  of  the  disease.  Finally,  in  a  large  propor- 
tion of  tuberculous  patients  neither  the  hemoglobin  nor  the  ery- 
throcytes fall  below  the  normal  standard,  this  being  the  rule  both 
in  incipient  cases,  and  in  those  which,  although  of  greater  chron- 
icity,  have  escaped  mixed  infection,  or  have  successfully  withstood 
the  ill  effects  of  the  constitutional  drain. 

In  25  hospital  cases  oi pulmonary  tuberculosis  in  various  stages, 
the  writer  found  the  hemoglobin  percentage  from  20  to  30  in  r; 
from  30  to  40  in  4,  from  40  to  50  in  4;  from  50  to  60  in  5  ; 
from  60  to  70  in  4 ;  from  70  to  80  in  6,  and  from  80  to  90  in  i . 
The  lowest  estimate  was  20,  and  the  highest  83  per  cent.  The 
erythrocytes  were  in  excess  of  5,000,000  in  3  cases;  from  4,000,- 

^  Deut.  med.  Woch.,  1901,  vol.  xxvii.,  p.  292. 


440  GENERAL    HEMATOLOGY.      ^ 

ooo  to  5,000,000  in  10;  from  3,000,000  to  4,000,000  in  1 1,  and 
from  2,000,000  to  3,000,000  in  i.  The  minimum  count  was 
2,660,000,  and  the  maximum  5,500,000  cells  per  cubic  millimeter. 

From  a  stud}^  o^  43  cases  of  coxalgia,  vertebral  tuberculosis^ 
and  tuberculous  osteo)?iyelitis,  Dane  ^  concludes  that  most  cases  of 
tuberculous  disease  of  the  bones  and  joints  do  not  cause  a  de- 
crease in  the  number  of  erythrocytes,  although  they  do,  however, 
affect  the  percentage  of  hemoglobin,  giving  rise  to  a  mild  degree 
of  "  chloro-anemia,"  so-called.  An  analysis  of  his  series  shows 
that  the  hemoglobin  percentage  ranged  from  80  to  90  in  2  cases  ; 
from  70  to  80  in  1 1  ;  from  60  to  70  in  24  ;  from  50  to  60  in  4; 
and  from  40  to  50  in  2.  The  er}^throcytes  numbered  5,000,000 
or  more  in  24  cases,  ranging  between  6,000,000  and  7,000,000 
plus  in  6;  from  4,000,000  to  5,000,000  in  15  ;  from  3,000,000 
to  4,000,000  in  3;  and  from  2,000,000  to  3,000,000  in  i.  Ac- 
cording to  P.  K.  Brown's  investigations  of  y^^  cases  of  bone 
tuberculosis,^  the  erythrocytes  decrease  only  in  long-continued 
and  extensiv^e  cases,  in  very  young  children,  and  in  secondary 
septic  infections,  while  the  hemoglobin  is  diminished  practically 
in  all  cases,  the  loss  depending  upon  the  same  factors  which  in- 
fluence the  er}^throcytes.  He  also  observed  that  the  patient's 
return  to  health  is  indicated  by  a  tendency  of  the  blood  to  re- 
turn to  the  normal  standard.  In  about  15  per  cent,  of  this 
author's  cases  there  was  an  erythrocyte  loss  of  one  million  or 
more  cells  per  cubic  millimeter,  and  in  all  but  some  half-dozen  the 
hemoglobin  was  diminished,  in  one  case  to  as  low  as  i  5  per  cent. 

In  cases  with  secondary  septic  infection  the  anemia  disappears 
as  the  patient's  recuperative  powers  become  active,  but  should  the 
latter  be  overwhelmed  by  the  intensity  of  the  pyogenic  process, 
the  anemia  either  remains  stationary  or  grows  more  marked. 

In  other  forms  of  the  disease — tuberculous  adenitis,  uicningitis, 
pericarditis,  pleurisy,  peritonitis,  and  lesions  of  the  genito-urinary 
system — the  changes  affecting  the  eiythrocytes  and  their  hemo- 
globin content  do  not  differ  from  those  already  described.  Well- 
developed  secondary  anemia  is  not  uncommon  in  the  two  last- 
named  forms  of  tuberculosis,  while  in  the  glandular  variety  dis- 
proportionately low  hemoglobin  values  are  frequently  found.  It 
is  to  be  recalled  that  apparent  polycythemia  may  be  encountered 
in  both  tuberculous  peritonitis  and  pleurisy,  due  in  the  former  in- 
stance to  the  inspissating  effect  of  the  purging,  and  in  the  latter 
to  the  same  effect  produced  by  the  sudden  accumulation  of  an 
extensive  exudate. 

1  Boston  Med.  and  Surg.  Journ.,  1896,  vol.  cxxxiv.,  pp.  529,  559,  and  589. 

2  Trans.  Med.  Soc.  of  State  of  California,  1897,  vol.  xxvii.,  p.  168. 


TUBERCULOSIS.  44 1 

Much  the  same  factors  which  influence  the 
Leucocytes,  erythrocytes  also  determine  the  behavior  of  the 
leucocytes  in  the  different  forms  of  tuberculo- 
sis. In  cases  of  unmixed  infection  these  cells  do  not  rise  above 
the  normal  limits  of  health,  but  the  moment  the  tuberculous 
lesion  becomes  complicated  by  a  secondary  infectious  process, 
such,  for  instance,  as  septicemia,  the  accident  is  heralded  by  a 
prompt  increase  in  their  number.  For  example,  in  a  simple 
tuberculous  adenitis  the  count  is  normal,  but  should  the  glands 
ulcerate,  fistulate,  and  become  septic,  a  leucocytosis  at  once  de- 
velops. As  a  rule,  the  qualitative  changes  are  inconspicuous, 
although  in  some  forms  of  the  disease,  as  will  be  shown  below, 
there  is  a  tendency  toward  lymphocytosis.  Increase  in  the 
number  of  leucocytes,  characterized  by  a  relative  gain  in  the 
lymphocytes  and  eosinophiles,  usually  develops  during  the  reac- 
tionary fever  following  the  injection  of  tuberculin. 

The  theory  that  the  occurrence  of  Neusser's  **  perinuclear 
basophilic  granules  "  during  the  course  of  the  disease  constitutes  a 
favorable  prognostic  sign,  has  been  effectually  exploded,  since 
later  research  has  proved  that  these  so-called  granules  are  simply 
artefacts.  (Seepage  176.)  /(?<^z;2<?/'/227^  cells  are  generally  found 
in  septic  cases,  but  they  are  absent  in  pure  tuberculosis. 

In  pulmonary  tuberculosis  leucocytosis  may  be  symptomatic 
either  of  cavities  or  of  rapidly  spreading  broncho-pneumonia,  and 
it  also  usually  follows  hemorrhage  of  any  considerable  extent. 
No  definite  relationship  apparently  exists  between  the  degree  of 
pyrexia  and  the  leucocyte  count.  Incipient  cases  of  simple  tu- 
berculous infiltration  and  pure  lung  cirrhosis  are  not  accompanied 
by  an  increase.  Of  the  25  cases  above  referred  to,  about  one- 
half  showed  a  moderate  leucocytosis,  in  12  the  count  being 
10,000  or  higher;  in  6  between  9,000  and  10,000  ;  in  2  between 
8,000  and  9,000  ;  and  in  2  between  3,000  and  8,000  per  cubic 
milHmeter.  The  highest  estimate  was  22,000,  and  the  lowest 
3,152.  Differential  counts  in  1 1  of  the  cases  having  an  increase 
of  10,000  or  more  revealed  no  qualitative  changes  other  than 
those  typical  of  an  ordinary  polynuclear  neutrophile  leucocytosis. 
It  may  be  added  that  in  6  of  these  1 1  counts  the  eosinophiles 
were  entirely  absent.  Myelocytes,  in  fractions  of  one  per  cent., 
were  found  in  cases  with  high-grade  anemia. 

A.  M.  Holmes  ^  believes  that  it  is  possible  to  estimate  not  only 
the  degree  of  the  tuberculous  process  but  the  degree  of  the  in- 
dividual's recuperative  powers,  by  a  careful  study  of  the  leuco- 

1  Second  Pan- Am.  Med.  Cong.,  City  of  Mexico,  Nov.  17,  1896.  Also,  Journ. 
Am.  Med.  Assn.,  1897,  vol.  xxix.,  p.  828. 


442 


GENERAL    HEMATOLOGY. 


cytes,  using  a  special  technique  of  staining  with  acid  and  basic 
dyes.  Briefly,  he  considers  that  the  pretuberculous  stage  is 
characterized  by  an  absence  of  leucocytosis,  a  slight  decrease  in 
the  lymphocytes,  little  or  no  increase  in  the  polynuclear  neutro- 
phils, more  or  less  abundant  debns  from  cell  disintegration,  and 
feeble  differentiating  powers  of  the  cells.  In  the  stage  of  early 
incipiency  he  finds  that  there  may  or  may  not  be  leucocytosis, 
accompanied  by  a  gain  in  the  polynuclear  neutrophiles  at  the  ex- 
pense of  the  lymphocytes  as  the  disease  advances,  together  with 
well-marked  signs  of  cell  disintegration  and  impaired  differentia- 
tion. In  the  advanced  stage,  with  cavity  formation  and  extensiv^e 
distribution  of  the  lesions  through  the  lungs,  the  preceding  signs 
are  thought  to  be  still  more  strongly  emphasized,  especially  those 
relating  to  the  quantity  of  debris  derived  from  cells  undergoing 
dissolution.  While  it  is  true  that  the  above  changes  in  the  leu- 
cocytes may  be  found  in  many  cases  of  pulmonary  tuberculosis, 
they  by  no  means  occur  in  all,  nor  can  they  be  regarded  as  char- 
acteristic of  this  disease.  Any  septic  or  purulent  process  may 
cause  a  similar  polynuclear  neutrophile  increase,  while  the  pres- 
ence of  degenerating  forms  of  cells  is  not  at  all  uncommon  in 
such  conditions. 

The  numerical  variations  in  the  leucocytes  in  coxalgia^  Potfs 
disease,  and  other  forms  oi  joint  and  bone  tuberculosis  are  well 
illustrated  by  the  following  analysis  of  the  large  number  of 
counts  made  by  Brown  ^  and  by  Dane  ^  in  these  conditions. 


r 

Leucocytes 

per  cb.  mm 

Brown's  122  Counts. 

Dane's  51  Counts. 

Above 

30,000 

in 

I 

4 

From 

20,000 

to 

30,000 

8 

12 

18,000 

20,000 

4 

I 

16,000 

18,000 

5 

2 

14,000 

16,000 

16 

4 

12,000 

14,000 

22 

12 

10,000 

12,000 

18 

7 

9,000 

10,000 

19 

3 

8,000 

9,000 

9 

I 

7,000 

8,000 

8 

I 

6,000 

7,000 

8 

4 

5,000 

6,000 

4 

0 

Maximum  : 

31,250 

41,369 

Minimum  : 

5,100 

6,063 

In  the  great  majority  of  instances  the  high  counts  picture  a 
polynuclear  neutrophile  leucocytosis,  but  this  is  not  invariably 
the   rule,  since  in  an  occasional  case  the   gain  depends  chiefly 


'  Loc.  cit. 


TUBERCULOSIS.  443 

Upon  an  increase  in  the  lymphocytes.  Low  counts  may  also 
be  characterized  by  a  relative  lymphocytosis,  this  change  being 
most  common  and  most  marked  in  young  children,  and  in  the 
profoundly  cachectic. 

From  the  results  of  the  painstaking  clinical  studies  made  by 
the  above-mentioned  writers,  it  may  be  concluded  that  in  these 
forms  of  bone  tuberculosis  high  leucocyte  counts  generally  sig- 
nify that  an  abscess  either  exists  or  impends,  although,  on  the 
contrary,  low  counts  do  not  necessarily  preclude  the  presence  of 
an  abscess.  High  counts,  especially  those  of  rapid  develop- 
ment, point  to  a  secondary  pyogenic  infection,  while  slowly 
developing,  moderate  leucocytoses  appear  to  be  compatible  with 
simply  a  sudden  increase  in  the  activity  of  the  tuberculous  proc- 
ess. In  the  presence  of  an  abscess,  low  counts  usually  indicate 
a  pure  tuberculous  pus  collection.  Cases  in  which,  at  the  first 
operation,  the  pus  was  proved  sterile,  show  an  increased  leuco- 
cyte count  when  the  wound  becomes  infected  with  pyogenic  bac- 
teria. In  these  post-operative  leucocytoses  due  to  secondary 
infection,  the  count  persists  very  high  for  a  few  days,  and  then 
gradually  falls  unless  the  sepsis  is  so  acute  as  to  threaten  life,  in 
event  of  which  it  may  still  remain  high  until  a  crisis  is  reached. 
Should  the  pyogenic  infection  be  so  severe  as  to  overcome  the 
patient's  resisting  powers,  the  leucocytosis  either  fails  to  develop, 
or  else  disappears.  As  in  pulmonaiy  tuberculosis,  the  leuco- 
gyte  count  and  the  degree  of  pyrexia  apparently  stand  in  no 
parallelism. 

Absence  of  a  leucocyte  increase  is  the  rule  in  uncomplicated 
acute  miliary  tuberculosis,  tiiberculoiis  adenitis,  pleurisy,  peritonitis, 
and  pericarditis,  whereas  in  tubercidosis  of  the  genito-tirinary  ap- 
paratus high  counts  are  not  uncommon,  owing  to  the  frequency 
of  secondary  infections  in  such  lesions.  In  tuberculous  menin- 
gitis the  behavior  of  the  leucocytes  is  not  constant,  although 
most  authors  report  a  well-defined  typical  leucocytosis,  ranging 
between  15,000  and  30,000  cells  to  the  cubic  millimeter. 

The  presence  of  a  leucocytosis  in  a  lesion  ob- 

DiAGNOSis.  viously  tuberculous,  whatever  its  seat,  is  usually 
to*  be  translated  as  a  sign  of  some  complicating 
secondary  infection,  the  chief  exceptions  to  this  general  rule  being 
those  infrequent  cases  in  which  the  sudden  extension  of  a  purely 
tuberculous  bone  disease  may  cause  a  moderate,  progressive  rise 
in  the  count.  A  positive  iodine  reaction  also  points  to  a  mixed 
infection.  In  pidmonary  tubercidosis,  if  the  influences  of  broncho- 
pneumonia and  hemorrhage  can  be  ruled  out,  leucocytosis  almost 
invariably  indicates  the  presence  of  cavity  formation,  and  in  bone- 


444  GENERAL    HEMATOLOGY. 

tuberculosis,  the  superposition  of  a  pyogenic  process.  In  perito- 
7ieal,  pleural,  and  pericardial  effusions  low  counts  suggest  an  un- 
mixed tuberculous  affection,  unless  the  leucopenic  influences  of  a 
virulent  infection  are  to  be  found.  The  diagnosis  between  acute 
miliary  tuberculosis  and  enteric  fever  has  been  referred  to  under 
the  latter  disease.  (See  page  331.)  Blood-cultures  should  be 
made  in  ever}^  case  of  doubtful  miliary  tuberculosis,  for  posi- 
tive results,  although  rare,  are  conclusiv^e  when  present.  The 
leucocyte  count  may  be  quite  as  high  in  tuberculous  as  it  is  in 
non-tuberculous  meni7igitis. 

LXIII.     TYPHUS    FEVER. 

Lewaschew  ^  claims  to  have  found  in  the  ex- 
Parasitology.  amination  of  the  finger  blood  of  a  large  number 
of  typhus  patients  a  micrococcus,  occurring  both 
singly  and  in  pairs,  which  he  characterizes  as  the  "  micrococcus 
exanthematicus,"  and  regards  as  the  pathological  agent  of  infec- 
tion. A  diplococcus  has  recently  been  isolated  by  Balfour  and 
Porter,^  from  blood  obtained  by  puncture  of  the  thumb,  in  36  out 
of  43  cases  of  typhus  examined  by  these  authors.  In  a  large 
number  of  control  cases,  including  measles,  scarlet  fever,  and  en- 
teric fever,  the  organism  in  question  was  uniformly  absent,  except 
in  the  last-named  disease  in  which  it  was  discovered  in  40  of  the 
46  cases  studied.  Cultures  of  this  parasite  when  injected  intrave- 
nously into  rabbits  produced  a  rapidly  fatal  septicemia  in  these 
animals.  These  investigations,  while  interesting  as  pathological 
studies,  throw  no  definite  light  on  the  etiology  of  typhus  fever. 

From  the  limited  data  at  present  available  con- 
Hemoglobin    cerning  the  blood  in  this  disease,  it  appears  that 
AND  at  the  beginning   of  the  attack   the   amount  of 

Erythrocytes,  hemoglobin  and  the  number  of  erythrocytes  re- 
main unchanged,  but  that  later  a  moderate  degree 
of  anemia  appears,  being  most  marked  during  the  period  of  apy- 
rexia.  Tumas'  careful  studies^  of  two  cases,  in  which  altogether 
twenty-five  examinations  were  made,  showed  a  hemoglobin  range 
of  from  50  to  94  per  cent.,  with  from  3,450,000  to  5,360,000 
er}'throcytes  per  cubic  millimeter,  the  minimum  figures  for  both 
being  obser\^ed  during  the  second  week  of  the  infection.  The 
presence  of  structural  degenerative  changes  and  of  erythroblasts 
has  not  been  recorded.  In  the  acutest  forms  of  the  disease  hemo- 
globinemia  has  been  noted. 

^  Vratch,  1894,  ns.  2  and  3.     Abstr. ,  Sajous'  Annual,  1895,  sec.  H.,  p.  45. 

2  Edinburgh  Med.  Journ.,  1S99,  vol.  vi.,  p.  522. 

3  Deut.  Arch.  f.  klin.  Med.,  1887,  vol.  xli.,  p.  323. 


VACCINATION.  445 

Absence  of  ieucocytosis,  with  occasional  counts 
Leucocytes,    showing  a  decided  leucopenia,  is  the  rule,  as  in 

enteric  fever,  according  to  conclusions  of  the 
most  careful  investigators  of  this  question.  Even  the  coexis- 
tence of  another  infection,  alone  sufficient  to  give  rise  to  Ieu- 
cocytosis, seems  to  have  no  effect  in  provoking  an  increase, 
as  evidenced  by  one  of  Tumas'  cases,  complicated  by  diph- 
theria, in  which  the  number  of  leucocytes  never  exceeded  9,600 
per  cubic  millimeter ;  in  his  other  case  they  once  rose  to 
17,000  after  a  profuse  sweat,  but  with  the  exception  of  this  in- 
stance the  counts  all  ranged  between  1,600  and  9,600.  Ew- 
ing^  found  a  maximum  count  of  9,000,  in  a  study  of  four  cases, 
two  of  which  were  fatal.  It  has  not  yet  been  determined 
whether  or  not  qualitative  changes  affecting  the  leucocytes  oc- 
cur in  this  disease. 

In  differentiating  typhus  fever  from  epidemic 
Diagnosis,     cei^ebro-spinal  ineyiingitis  the  presence  of  a  frank 

Ieucocytosis  should  be  regarded  as  highly  symp- 
tomatic of  the  latter.  The  behavior  of  the  leucocytes  fails  to  be 
of  service  in  distinguishing  typhus  from  typhoid,  since  in  neither 
of  these  infections  are  these  cells  increased  in  number ;  here,  how- 
ever, the  serum  test  usually  proves  of  signal  utility.  Absence  of 
Ieucocytosis  is  also  associated  with  malignant  measles,  the  early 
stages  of  which  may  remind  one  of  typhus  fever. 


LXIV.     VACCINATION. 

Billings^  who  has  recently  investigated  the  effects  of  vacci- 
nation on  the  blood,  finds  that  no  changes  are  produced  in  the 
he}}wglobi7i  and  erythrocytes  by  this  procedure.  Moderate,  but 
definite  Ieucocytosis,  the  counts  averaging  about  15,000  per 
cubic  millimeter,  is  characteristic.  The  Ieucocytosis  is  of  the 
inflammatory  type,  and  reaches  its  maximum  coincidentally  with 
the  height  of  maturation  of  the  vaccine  pustule,  fading  away 
as  the  latter  desiccates.  Sobotka  ^  finds  the  same  alterations, 
and  has  also  observed  a  secondary  Ieucocytosis,  beginning 
about  the  tenth  or  twelfth  day,  and  often  persisting  for  as  long 
as  six  days,  the  height  of  the  count  corresponding  in  a  general 
way  to  the  severity  of  the  local  lesion,  and  to  the  activity  of  the 
virus. 

'"Clinical  Pathology  of  the  Blood,"  Phila.  and  N.  Y.,  1901. 
2  Med.  News.  1898,  vol.  Ixxiii.,  p.  301. 
^Zeitschr.  f.  Heilk..,  1893,  vol.  xiv. ,  p.  349. 


44^  GENERAL    HEMATOLOGY. 

LXV.     VALVULAR   HEART    DISEASE. 

In  well-compensated  valvular    lesions  of  the 

Stage  of      heart,  irrespective   of  their  character,  the  blood 

Compensation,  shows  no  deviation  from  its  normal  composition, 

for  such  lesions  of  themselves  are  incapable  of 

giving  rise  to  blood  changes.      If  the  latter  are  observed  in  cases 

of  this   kind  they  should  be  attributed  to  other  factors,  rather 

than  to  the  heart  disease. 

In  cases  associated  with  acute  failure  of  com- 
AcuTE  Rup-  pensation,  however,  changes  in  the  blood-picture, 
TURE  OF  the  intensity  of  which  runs  parallel  to  the  severity 
Compensation,  of  the  circulatory  disturbances,  sooner  or  later  be- 
come manifest.  These  changes,  consisting  in  the 
production  of  a  so-called  serous  plethora,  depend  chiefly  upon  a  re- 
duction in  blood  pressure,  in  consequence  of  which  the  blood  mass 
becomes  diluted  by  transudation  into  the  vessels  of  fluids  from  the 
surrounding  lymph  spaces.  It  is  also  highly  probable  that  this 
surcharging  of  the  blood  mass  with  liquids  is  aggravated  by  the 
disturbances  in  the  functions  of  the  heart  and  kidneys  whereby 
the  elimination  of  the  superfluous  watery  constituents  of  the  blood 
is  hindered.  Oertel  ^  remarks  that  it  seems  not  unlikely  that  an- 
other factor  in  the  production  of  this  hydremia  may  be  found  in 
the  increased  consumption  of  liquids,  which  he  has  noted  in  many 
patients  suffering  from  valvular  disease.  Examination  of  the 
blood  at  this  stage  of  the  disease  shows  that  there  is  a  diminution 
in  the  albuminoid  constituents  and  in  the  specific  gravity  of  the 
blood,  that  the  percentage  of  hemoglobin  falls,  and  that  oligo- 
cytJieinia  proportionate  to  the  latter  develops  ;  the  leucocytes,  un- 
like the  erythrocytes,  do  not  decrease,  but  their  number  remains 
within  normal  limits.  The  observer  must  be  careful  not  to  mis- 
take the  blood-picture  of  hydremia  for  that  of  a  true  anemia,  from 
which  it  is  distinguishable  only  by  taking  into  consideration  other 
clinical  signs  and  symptoms. 

In  cases  of  chronic  valvular  disease  with  stasis. 
Effects  of     dyspnea,  and  cyanosis,  a  very  different  picture 
Stasis.         from    that   just    described    presents   itself     The 
hydremia    gives    way  to   a  concentration  of  the 
blood  mass,  this  change  being  due  mainly  to  the  increased  outflow 
of  plasma  from  the  vessels  into  the  neighboring  tissues,  and  per- 
haps to  the  excessive  loss  of  water  especially  through  the  lungs, 
as  Grawitz-  has  suggested.     Stengel^  offers  as  an  explanation  of 

>  Deut.  Archiv.  f,  klin.  Med.,  1892,  vol    xxxi.,  p.  293. 

2  Loc.  cit 

3Proc.  Path.  Soc.  of  Phila.,  1898,  n.  s.,  vol.  i.,  p.  137. 


VARICELLA.  447 

this  inspissation  of  the  blood  two  other  factors  :  the  lagging  of 
the  erythrocytes  in  the  peripheral  arterioles  and  venules,  and  the 
increase  in  the  viscosity  of  the  blood.  At  this  period  of  valvular 
disease  the  specific  gravity  and  the  proportion  of  albuminoid 
principles  of  the  blood  rise,  and  high  hemoglobin  values  with 
more  or  less  decided  polycythemia  are  found,  the  erythrocyte 
count  commonly  being  in  the  neighborhood  of  6,000,000  per 
cubic  millimeter,  or  in  some  instances,  notably  those  of  congenital 
heart  disease,  as  high  as  from  7,000,000  to  8,000,000.  Such  a 
polycythemia,  it  should  be  remembered,  may  be  sufficient  com- 
pletely to  mask  a  coexisting  anemia ;  in  fact,  it  must  be  admitted 
that  no  reliable  data  concerning  the  true  condition  of  the  blood 
are  obtainable  in  valvular  disease  of  the  heart,  except  during  the 
stage  of  perfect  compensation.  The  behavior  of  the  leucocytes  is 
capricious  :  their  number  may  be  normal,  or,  on  the  other  hand, 
a  decided,  but  not  an  excessive,  leucocytosis  may  be  present. 
Should  this  be  the  case,  the  increase  will  be  found  to  involve 
principally  the  polynuclear  neutrophile  cells  at  the  expense    of 

the  other  forms. 

Grawitz^  has  drawn  attention  to  the  fact  that  a  form  of  stroma 
degeneration  may  frequently  be  met  with  under  these  circum- 
stances, being  evidenced  by  the  unnatural  readiness  with  which 
the  hemoglobin  tends  to  become  diffused  in  the  plasma  within  a 
short  time  after  the  removal  of  the  blood  from  the  body.  This, 
while  it  cannot  be  termed  a  true  hemoglobinemia,  at  least  appears 
to  demonstrate  that  the  stroma  and  its  hemoglobin  are  less 
firmly  combined  than  they  are  in  perfectly  normal  blood. 

The  efforts  made  by  some  authors  to  associate  certain  blood 
conditions  with  definite  valvular  lesions  seem  to  the  writer  far- 
fetched. The  changes  just  described  are  thought  by  some  to  be 
especially  prone  to  occur  in  affections  of  the  mitral  segments, 
and  other  authors  even  go  so  far  as  to  state  that  disease  of  these 
valves  is  more  often  associated  with  transient  apparent  anemia  or 
with  chronic  polycythemia  than  lesions  of  the  aortic  valves,  the 
blood  in  the  latter  conditions  being  usually  normal,  or  but 
slightly  impoverished.  After  all,  the  general  disturbances  de- 
pendent upon  the  lesion,  and  not  the  lesion  per  se  account  for  the 
alterations  of  the  normal  blood-picture  which  have  been  observed 
in  heart  disease  of  this  type. 

LXVI.     VARICELLA. 
The  only  observation  on  record  appears  to  be  that  of  Engel,^ 
who  found  in  a  child  of  five  years,  at  the  height  of  the  pustular 

^  Loc.  cit. 

2 XV.   Cong.  f.  inn.  Med.,  1897. 


448  GENERAL    HEMATOLOGY. 

stage,  6^  per  cent,  of  polynuclear  neutrophiles,  and  an  absence 
of  eosinophiles.  After  the  healing  of  most  of  the  pustules,  three 
days  later,  the  percentage  of  polynuclears  was  47,  and  that  of  the 
eosinophiles  16.   Numerical  estimates  in  this  case  are  not  recorded. 

LXVII.      VARIOLA. 

During  the  first  few  days  of  the  attack  the  fibrin 
General       network  is  normal,  but  as  the  stage  of  pustular 
Features,      eruption  is  reached,  a  decided  Jiyperinosis  develops. 
Streptococci  have  been  found  in  the  blood  repeat- 
edly by  Widal  and  Benzacon.*    Pfeiffer "  has  attached  specific  prop- 
erties to  apparently  ameboid  bodies  which  he  discovered  in  small- 
pox patients'   blood,  and  other  amebae  have  been  found  under 
similar  circumstances  by  Reed,^  by  Weber,*  and  others.      None 
of  these  discoveries  have  elucidated  the  etiology  of  variola. 

Post-febrile   anemia,   first    becoming    apparent 

Hemoglobin    when  deferv^escence  is  established,  is  the  rule  in 

AND  the  majority  of  cases,  the  decrease  in  hemoglobin 

Erythrocytes,  and  corpuscles   being  usually  decided,  and  not 

infrequently  excessive.     This  is  especially  true  in 

hemorrhagic  and  confluent  variola,  in  which  conditions  a  loss  of 

two  or  three  million  cells  per  cubic  millimeter  may  occur  with 

great  rapidity.     The  loss  of  hemoglobin  begins  slightly  earlier 

than  that  of  the  corpuscles,  but  later  both  elements  are  usually 

diminished  proportionately. 

During  the  febrile  period  of  the  disease,  the  number  of  eiythro- 
cytes  is  approximately  normal,  or  even  increased,  in  case  the 
blood  becomes  concentrated  by  the  influence  of  the  temperature. 
Qualitative  changes  in  the  er}'throcytes  are  not  marked,  except 
in  cases  with  severe  anemia,  in  which  poikilocytosis  and  deform- 
ities of  size  may  be  noted.  In  such  instances  hemoglobinemia 
may  also  be  detected  occasionally.  Regeneration  of  the  blood 
is  said  to  be  exceedingly  slow. 

From  the  studies  of  Halla  and  Brouardel,  and 
Leucocytes,  of  Pick,  quoted  by  von  Limbeck,^  it  appears  that 
the  influence  of  a  variolous  infection  does  not  of 
itself  cause  leucocytosis,  a  fact  which  is  evident  for  the  reason  that 
during  the  height  of  the  initial  fever,  in  the  early  eruptive  stage  of 
even  well-marked  cases,  increase  in  the  number  of  leucocytes 
does  not  occur.  But  as  pustulation  begins,  and  secondar}^  infec- 
tion with  pyogenic  micro-organisms  occurs,  an  increase  in  the  leu- 

^Centralbl.  f.  allg.  Path.,  1896,  vol.  vii.,  p.  569. 
2  Handb.  d.  spec.  Therap. ,  1894,  vol.  i. ,  p.  229. 
3Journ.  of  Exper.  Med.,  1897,  vol.  ii.,  p.  515. 
*Centralbl.   f.  Bakt.  u.  Parasit.,  1897,  vol.  xxi.,  p.  286. 
5  Loc.  cit. 


YELLOW    FEVER.  449 

oocytes  takes  place,  the  leucocytosls  as  a  rule  increasing  propor- 
tionately to  the  gravity  of  the  infection.  As  in  other  infections, 
veiy  mild  and  very  virulent  cases  do  not  give  rise  to  an  increase. 
In  the  average  case,  such  as  that  quoted  by  von  Limbeck,^  the 
leucocytes,  normal  at  the  beginning  of  the  illness,  number  about 
1 1,000  or  12,000  per  cubic  millimeter  by  the  time  the  eruption 
becomes  pustular,  the  maximum  count  of  .these  cells,  about  20,000, 
being  attained  coincidentally  with  full  maturation  of  the  pustules. 
As  desiccation  progresses,  the  number  of  leucocytes  gradually  falls, 
the  normal  count  again  being  reached  during  the  end  of  the  second 
or  the  beginning  of  the  third  week.  Varioloid^  unless  associated 
with  suppuration,  does  not  cause  leucocytosis.  Most  authors  have 
found  that  the  increase  involves  chiefly  the  polymorphous  for^ns 
of  leucocytes,  and  that  the  percentage  of  uionomiciear  cells  is 
proportionately  decreased.  On  the  other  hand,  Courmont  and 
Montagard"  insist  that  in  uncomplicated  cases  the  increase  in- 
volves the  mononuclear  forms;  even  during  the  pustular  stage, 
when  abscesses  or  furunculosis  coexisted,  they  found  the  gain 
mononuclear  in  type.  In  severe  infections  it  is  common  to  find 
small  numbers  of  myelocytes.  WeiP  has  also  found  these  same 
changes,  and  lays  special  stress  upon  the  occurrence  of  myelo- 
cytes as  a  diagnostic  sign  of  this  exanthem. 

The  blood  plaques  are  decreased  in  number  during  the  period  of 
fever,  being  sometimes  absent  from  the  blood  at  this  stage  of  the 
disease. 

Unfortunately,  the  blood  examination  is  of  no 

Diagnosis,  value  in  differentiating  variola  from  a  number  of 
other  diseases  which  may  more  or  less  closely 
resemble  it.  For  example,  the  prepustular  stage  of  the  disease 
has  been  mistaken  for  measles,  but  in  both  there  is  an  absence  of 
leucocytosis ;  again,  the  pustular  stage  of  small-pox  may  be 
counterfeited  by  varicella,  pustidar  syphilide,  and  the  purpuric 
form  of  cerebrospinal  meningitis,  and  all  of  these  conditions  are 
accompanied  by  a  well-marked  leucocytosis. 

LXVIII.     YELLOW  FEVER. 

Slow  coagulation  and  deficiency  or  even  com- 

General      plete  absence  of  the  fibrin  fietzvork  is  common. 

Features,      these  peculiarities  being  observable  often  in  the 

earliest  stages  of  the  disease,  apparently  beginning 

coincidentally  with  the  introduction  of  the  infecting  principle. 

^  Loc.  cit. 

2  Province  med.,  1900,  vol.  xv.,  p.  481. 
■■^Sem.  med.,  1900,  vol.  xx.,  p.  222. 
29 


450  GENERAL    HEMATOLOGY. 

The  identit}^  of  the  specific  cause  of  this  disease  is  a  current 
topic  of  heated  controversy.  SanarelH's  claim/  that  his  bacillus 
icteroides  is  to  be  found  in  the  circulating  blood  of  yellow  fever 
patients  during  life,  has  been  flatly  contradicted  by  several  investiga- 
tors, notably  by  Agramonte,-  and  by  the  members  of  the  United 
States  Yellow  Fever  Commission,^  Reed,  Carroll,  Agramonte,  and 
Lazear,  whose  several  reports  show  an  uniform  failure  to  isolate 
Sanarelli's  bacillus  either  by  ante-mortem  blood  cultures,  or  by 
post-mortem  examinations  of  the  blood  and  organs.  In  passing,  it 
may  be  of  interest  to  add  that  Finlay's  theor}^^  that  yellow  fever 
is  transmitted  by  means  of  the  mosquito's  bite,  has  been  con- 
firmed beyond  question  by  the  experiments  of  this  Commission, 
which  has  identified  the  Stegomyia  fasciata  d^s  the  offending  insect. 
Archinard  and  Wood  ^  claim  that  in  a  study  of  50  cases  of  yel- 
low fever,  the\'  obtained  a  positive  serum  reaction  with  the  bacil- 
lus icteroides  in  about  75  per  cent,  of  the  tests.  In  low  dilutions 
(1:5,  for  instance)  they  found  that  the  blood  of  yellow  fever 
patients  also  clumped  cultures  of  the  typhoid  bacillus. 

Pothier's    studies   of    154    cases   at    the   New 

Hemoglobin    Orleans  Isolation  Hospital,  in  1897,^  show  that  a 
AND  more  or  less   decided  loss  of  hemoglobin  com- 

Ervthrocvtes.  monly  occurs  during  the  active  stages  of  the  in- 
fection, and  that  the  normal  percentage  is  slowly 
regained  during  and  after  convalescence  ;  during  the  febrile  period 
the  hemoglobin  ranged  from  50  to  90  per  cent.,  and  during  con- 
valescence from  64  to  So  per  cent.  He  found  that  the  er}'thro- 
cyte  count  never  fell  below  4,280,000  per  cubic  millimeter,  and 
that  even  in  a  fatal  case  it  might  be  normal.  Sternberg  ^  has  also 
noted  the  absence  of  quantitative  changes  affecting  the  erythro- 
cytes in  this  disease,  stating  that  *'  although  there  is  no  general 
destruction  of  the  red  corpuscles,  it  is  probable  that  a  consider- 
able number  of  these  elements  perish,  for  the  serum  contains  free 
hemoglobin,  which  gives  it  a  yellow  color  even  as  early  as  the 
third  or  fourth  day."  This  hemoglobinemia  is  common  in  all 
cases,  but  especially  so  in  fatal  cases  just  before  death.     The  re- 

'  Annal.  de  I'lnstitut  Pasteur,  1897,  vol.  xi.,  p.  433.     Also,  British  Med.  Journ., 
1897,  vol.  ii.,  p.  7.     Also,  Med.  Record,  1897,  vol.  lxii.,p.  117. 

*  Med.  News,  1900,  vol.  Ixxvi.,  p.  249. 

3  Phila.    Med.  Journ.,  1900,    vol.    vi.,  p.   790.     Also,  Journ.  Am.    Med.    Assn., 
1 901,  vol.  xxxvi.,  p.  431. 

♦  Pan- Am.   Med.  Cong.,   Havana,  Feb.  4,  1901.    Also,  Journ.    Am.  Med.  Assn., 
1901,  vol.  xxxvi.,  p.  1040. 

=  New  Orleans  Med.  &  Surg.  Journ.,  1898,  vol.  1.,  p.  455, 
^  Journ.  Am.  Med.  Assn.,  1898,  vol.  xxx.,  p.  S85. 

^  U.  S.  M.  H.  Service   Report  on    the   Etiology  and   Prevention  of  Yellow  Fever, 
Washington,  1S90.  >^ 


YELLOW    FEVER.  4^1 

suits  of  these  investigations  by  Pothier  and  by  Sternberg  are  con- 
tradictory to  the  views  expressed  by  earlier  writers,  who  have 
been  accustomed  to  describe  the  cellular  elements  of  the  blood 
in  yellow  fever  as  profoundly  altered. 

Decided  degenerative  changes  in  the  erythrocytes  have  not  been 
observed,  although  it  has  been  asserted  by  Jones  ^  that  these 
cells  "  present  under  the  microscope  certain  peculiar  appearances 
which  are  referable  to  the  action  of  certain  extraneous  excretory 
matters  in  the  blood."  A  few  nucleated  cells  of  the  normoblas- 
tic type  are  reported  to  have  been  found  occasionally. 

The  behavior  of  the  leucocytes  in  yellow  fever 
Leucocytes,  is  extremely  variable,  their  number  being  sub- 
normal in  some  cases,  and  decidedly,  but  not 
strikingly,  increased  in  others.  In  the  series  of  Pothier,  just 
quoted,  the  counts  ranged  between  4,660  and  20,000  per  cubic 
millimeter.  The  increase,  when  present,  involves  chiefly  the 
polynuclear  neutropJiiles,  the  relative  proportion  of  these  cells 
usually  being  in  excess  of  85  or  90  per  cent.  Small  numbers  of 
myelocytes  were  found  occasionally  by  Cabot  ^  in  differential 
counts  of  twelve  films  of  yellow  fever  blood. 

Sternberg  ^  has  described  certain  relatively  large,  highly  refrac- 
tive, spherical  granules  in  the  protoplasm  of  the  leucocytes, 
which  he  is  inclined  to  regard  as  an  evidence  of  fatty  degenera- 
tion of  these  cells  ;  these  granules  were  especially  abundant  in 
severe  cases,  nearly  every  leucocyte  containing  some  of  them. 
They  are  not,  however,  peculiar  to  yellow  fever,  since  they  have 
been  found  in  the  blood  of  patients  suffering  from  beri-beri,  and 
even  in  the  blood  of  normal  individuals,  residents  of  the  tropics. 
If  SanarelH's  claims  stand  the  test  of  time, 
Diagnosis,  blood  culturing  and  the  clump  reaction  should 
prove  of  the  greatest  value  in  differentiating  this 
infection  from  those  obscure  forms  of  dengue  of  which  it  may  be 
a  faithful  clinical  counterfeit.  The  frequency  of  hemoglobinemia 
in  yellow  fever  and  its  absence,  so  far  as  is  known,  in  dengue, 
may  also  serve  as  a  hint  of  some  importance.  In  differentiating 
vialarial fever,  the  examination  of  the  blood  for  the  malarial  par- 
asite will  usually  give  definite  information,  and  the  occasional 
presence  of  a  well-developed  polynuclear  leucocytosis  in  yellow 
fever  should  not  be  forgotten. 

^Journ,  Am.  Med.  Assn.,  1895,  vol.  xxiv.,  p.  403. 
2Loc.  cir. 
^Loc.  cit. 


INDEX  OF   SUBJECTS. 


ABSCESS,  295 
■^    coagulation,  295 
color  index,  295 
diagnosis,  297 
erythrocytes,  295 
fibrin,  295 
hemoglobin,  295 
iodin  reaction,  295 
leucocytes,  296 
normoblasts,  296 
Absence  of  leucocytosis,  185 

in  acute  infections,  188 
in  enteric  fever,  328 
in  influenza,  354 
in  leprosy,  358 
in  malarial  fever,  382 
in  Malta  fever,  394 
in  measles,  395 
in  tuberculosis,  441 
significance  of,  188 
Acetanilid  poisoning,  416 
Acetone,  test  for,  1 10 
Acetonemia,  iio 
Achalme's  bacillus,  422 
Achroiocythemia,  121 
Achromacytes,  138 
Acid  dyes,  59 
Acidity  of  blood  in  Asiatic  cholera,  304 

in  insolation,  356 
Acromegaly,  298 
Actinomycosis,  298 
Acute  yellow  atrophy  of  the  liver,  298 
Addison's  disease,  299 
Adenitis,  197,  443 
Ague  cake,  274 
Alcohol  and  ether  fixation,  62 
fixation,  62 
poisoning,  416 
Alcoholic  neuritis,  402 
Alexines,  185 
Alkalimeter,  Engel's,  77 
Alkalinity,  77,  95 

estimation  of,  77 

in  Asiatic  cholera,  304 

in  chlorosis,  210 

in  diabetes  mellitus,  309 

in  erysipelas,  332 

in  fever,  334 

in  gout,  347 

in  hemorrhagic  diseases,  348 

in  Hodgkin's  disease,  267 


Alkalinity  in  icterus,  353 

in  infantile  enteric  fever,  290 
in  insolation,  356 
in  lymphatic  leukemia,  256 
in  nephritis,  399 
in  osteomalacia,  406 
in  pernicious  anemia,  220 
in  rheumatism,  422 
in  scurvy,  348 
in  secondary  anemia,  237 
in  spleno-medullary  leukemia,  247 
Altitude,  effect  on  blood,  133 
Altmann's  bioblastic  theory,  158 
Ammonia  poisoning,  416 
Amphophile  granules,  157 
Amyloid  disease,  392 
Amyl  nitrite  poisoning,  416 
Analysis,  centrifugal,  72 
Anopheles,  360 
Anemia,  113 

bothriocephalus,  356 
brick-makers',  357 
classification  of,  1 14 
following  splenectomy,  272 
from  ankylostomiasis,  357 
from  gastric  tubule  atrophy,  343 
from  helminthiasis,  356 
from  threadworms,  356 
from  thyroidization,  399 
in  appendicitis,  300 
in  gastric  cancer,  386 
in  hemorrhagic  diseases,  349 
in  malignant  disease,  391 

endocarditis,  393 
in  nephritis,  400 
in  rheumatic  ifever,  422 
in  sepsis,  429 
in  tuberculosis,  439 
in  variola,  448 

infantum  pseudo-leukemica,  290 
miners',  357 
pathogenesis  of,'il5 
pernicious,  218 
post-hemorrhagic,  239 
post-malarial,  381 
post- typhoid,  326 
primary,  I15 
pseudo-,  113 
secondary,  236 
splenic,  231 
syphilitic,  432 


454 


INDEX     OF     SUBJECTS. 


Anemia  toxic,  416 

tropical,  1 14 
Anemias  of  infancy  and  childhood,  279 

classification,  283 

frequency,  282 

gastrointestinal,  289 

general  characteristics,  283 

leukemia,  284 

mild.  287 

pernicious,  284 

post- typhoid,  289 

primary,  284 

rachitic,  288 

secondary,  287 

severe,  287 

splenic  enlargement,  283 

syphilitic,  288 

tuberculous,  289 

von  Jaksch's,  290 

with  leucocytosis,  287 
Aneurism,  297 
Anhydremia,  106 
Aniline  dyes,  59 
Ankylostomiasis  anemia,  357 
Anthrax,  299 
Antipyrin  poisoning,  416 
Antipyretics,  effects  on  leucocytes,  414 

erythrocytes,  123 
Aortic  lesions,  447 
Appendicitis,  300 

anemia,  300 

diagnosis,  302 

leucocytosis,  301 
Arloing  and  Courmont's  reaction,  437 
Arsenic,  effect  on  blood,  12 1 
Arseniuretted  hydrogen  poisoning,  416 
Arthritis,  septic,  423 
Ascites,  351 

chylous,  335 

effect  on  blood,  351 
Asiatic  cholera,  304 
Aspidium  poisoning,  416 
Asthma,  305 

Atmospheric  cold,  effect  on  blood,  181 
Atrophic  hepatic  cirrhosis,  350 
Atypical  erythroblasts,  146 
Axillary  abscess,  296 

DACTERIEMIA,  in 

*^     in  infants,  292 

Bacteria  found  in  the  blood,  112 

in  anthrax,  299 

in  beri-beri,  402 

in  bubonic  plague,  306 

in  cerebro- spinal  meningitis,  398 

in  cholelithiasis,  308 

in  enteric  fever,  317 

in  glanders,  346 

in  influenza,  354 

in  leprosy,  358 


Bacteria  found  in  malignant  endocarditis, 
392 

in  Malta  fever,  394 

in  measles,  395 

in  nephritis,  399 

in  pneumonia,  411 

in  purpura,  348 

in  relapsing  fever,  419 

in  rheumatism,  422 

in  scarlet  fever,  424 

in  scurvy,  348 

in  sepsis,  428 

in  tuberculosis,  437 

in  typhus  fever,  444 

in  variola,  448 

in  yellow  fever,  450 
Bactericidal  action  of  blood,  185 
Bacteriological  examination,  83 
Banti's  disease,  231 
Barlow's  disease,  348 
Basedow's  disease,  233 
Basic  dyes,  59 
Basophil e  granules,  157 
Basophil  es,  166 

in  Addison's  disease,  299 

in  carcinoma,  389 

in  lymphatic  leukemia,  260 

in  sarcoma,  391 

in  spleno-medullary  leukemia,  256 
Basophilia,  202 

granular,  147 

perinuclear,  176 
Baths,  effect  on  blood,  l8i 
Benario's  method  of  fixation,  62 
Biermer's  disease,  218 
Bile  in  the  blood,  no 

test  for,  no 
Bioblastic  theory,  Altmann's,  158 
Blackwater  fever,  383 
Blastomycetes  in  carcinoma,  385 
Bleeders,  21 
Blood,  arterial  and  venous,  94 

at  birth,  2S0 

carbonic  acid,  94 

color,  94 

concentration,  149 

crisis,  143 

crystals,  1 19 

cultures,  83,  112 

dust,  151 

extractives,  94 

fats,  94 

fetal,  279 

filaria,  335 

gases,  94 

general  composition.  93 

laked,  94 

lancet,  20 

odor,  95 

oxygen,  94 


INDEX     OF     SUBJECTS. 


455 


Blood  plaques,  150 

counting  the,  7  i 

in  bubonic  plague,  308 

in  chlorosis,  216 

in  diabetes  mellit\is,  312 

in  enteric  fever,  ^^  i 

in  erysipelas,  332 

in  hemorrhagic  diseases,  350 

in  Hodgkin's  disease,  269 

in  lymphatic  leukemia,  260 

in  malarial  fever,  384 

in  measles,  395 

in  pernicious  anemia,  228 

in  pneumonia.  415 

in  post-hemorrhagic  anemia,  241 

in  scarlet  fever,  426 

in  secondary  anemia,  239 

in  spleno-medullary    leukemia, 

256 
in  splenic  anemia,  233 
in  variola,  449 
nature,  150 
normal  number,  15 1 
pathological  variations,  151 
plasma,  93 
proteids,  93 
quantity,  93 
quotient,  122 
reaction,  95 
regeneration,  241 

after  splenectomy,  272 

after  treatment  with  suprarenal 

extract,  299 
in  anemias  of  children,  283 
in  cai-cinoma,  386 
in  diphtheria,  312 
in  enteric  fever,  327 
in  malarial  fever,  379 
in  pernicious  anemia,  221 
in  post-hemorrhagic  anemia,  241 
in  scarlet  fever,  425 
in  variola,  448 
salts,  93 
serum,  93 
specific  test  for,  88 
spectra,  125 
viscosity,  95 
Bone  marrow,  128 

in  leucocytosis,  187 
Bordet's  reaction,  88 
Bothriocephalus  anemia,  356 
Brain,   abscess,  402 
hemorrhage,  402 
tumor,  402 
Breast,  carcinoma  of,  388 
Bremer's  test,  310 
Bromine  poisoning,  416 
Bronchitis,  306 
Bubonic  plague,  306 
Buddingofprotoplasm  of  lymphocytes,  259 


CACHEXIA,  malarial,  383 
^     Capillary  bronchitis,  306 
Carbon  monoxide  hemoglobin,  125 
spectrum  of,  125 
test  for,  126 
Carbuncle,  189 
Carcinoma,  384 

alkalinity,  385 

coagulation,  384 

color  index,  386 

deformed  erythrocytes,  387 

diagnosis,  391 

digestion  leucocytosis,  388 

erythroblasts,  387 

erythrocytes,   385 

fibrin,  384 

gastric,  388 

hemoglobin,  385 

hepatic,  388 

leucocytes,  387 

mammary,  388 

metastases,  387 

polycythemia,  386 

protozoa,  385 

rectal,  388 

regeneration,  386 

renal,  387 

specific  gravity,  385 

sugar,  385 

uterine,  3S8 
Castration,  effect  on  blood,  201 
Catarrhal  pneumonia,  306 
Cecum,  malignant  disease  of,  303 
Cellular  elements  of  blood,  93 

plethora,  105 
Centrifugal  analysis,  73 
Cerebral  abscess,  296 
Cerebro-spinal  meningitis,  396 
Cervical  abscess,  296 
Charcot-Leyden  crystals  in  leukemia,  246 
Chemical  fixation,  62 
Chemotaxis,  184 
Chicken-pox,  447 
Chloral  poisoning,  416 
Chloro-anemia,  237 
Chlorosis,  209 

alkalinity,  210 

appearance  of  fresh  blood,  209 

blood  plaques,  216 

coagulation,  209 

color  index,  210 

diagnosis,  216 

Egyptian,  357 

eosinophiles,  215 

erythroblasts,  213 

erythrocytes,  210 

florid  a,  217 

granular  basophilia,  213 

hemoglobin,  210 

heredity,  217 


456 


INDEX     OF     SUBJECTS. 


Chlorosis,  leucocytes,  214 

male,  217 

microcytosis,  213 

myelocytes,  215 

pallor  of  erythrocytes,  213 

poikilocytosis,  213 

polychromatophilia,  213 

polynuclear  neutrophiles,  215 

relative  lymphocytosis,  215 

sex,  217 

specific  gravity,  209 

symptoms,  217 

syphilitic,  432 

transitional  forms,  215 

volume  of  blood,  209 

without  blood  changes,  217 
Cholelithiasis,  308 
Cholemia,  no 
Chorea,  405 
Chromic  acid  fixation,  62 

poisoning  by,  416 
Chyluria,  parasitic,  355 
Cirrhosis  of  the  liver,  350 
Class'  diplococcus,  434 
Coagulation,    100 

in  abscess,  295 

in  acromegaly,  298 

in  carcinoma,  384 

in  chlorosis,  209 

in  cholelithiasis,  308 

in  fever,  334 

in  hemophilia,  349 

in  Hodgkin's  disease,  267 

in  icterus,  353 

in  infantile  enteric  fever,  290 

in  lymphatic  leukemia,  256 

in  nephritis,  399 

in  obstructive  jaundice,  353 

in  pernicious  anemia,  219 

in  pneumonia,  411 

in  rheumatic  fever,  421 

in  sarcoma,  389 

in  scarlet  fever,  423 

in  secondar}'  anemia,  236 

in  spleno-medullary  leukemia,  247 

in  yellow  fever,  449 

time,  estimation  of,  79 
Coagulometer,  Wright's,  80 
Color  index,  122 

of  the  blood,  94 

in  aniline  poisoning,  95 

in  carbon  monoxide  poisoning, 

95 
in  chlorosis,  209 
in  diabetes  mellitus,  309 
in  dyspnea,  95 
in  Hodgkin's  disease,  267 
in  icterus,  353 
in  lymphatic  leukemia,  256 
in  nitrobenzol  poisoning,  95 


Color  of  the  blood  in  pernicious  anemia, 
218 
in  hydrocyanic  acid  poisoning,95 
in  potassium  chlorate  poisoning, 

95 
in  secondary  anemia,  236 
in  splenic  anemia,  231 
in    spleno-medullary    leukemia, 

246 
in  sulphuretted  hydrogen  poison- 
ing, 95 
normal  variations,  94 
pathological  variations,  94 
Coma,  diabetic,  309 
Concentration  of  the  blood,  149 
Convulsions,  404 
Corpuscles,  Eichhorst's,  137 
phantom,  138 
Ponfick's,  138 
Corrosive  metals  and  minerals,  poisoning 

by,  416 
Counting  chamber,  Thonia-Zeiss,  43 
Zappert,  44 
differential,  70 
the  blood  plaques,  71 
the  erythrocytes,  45,  54,  55 
the  leucocytes,  49,  53,  55 
Cover-glasses,  cleaning  the,  22 
Coxalgia,  440 
Crenation,  126 
Crisis,  blood,  143 
Crj'stals,  Charcot-Leyden,  24 

Teichmann's,  120 
Culex,  361 

Cultures,  blood,  83,  112 
Cyanosis,  effect  on  blood,  150 
Cyst,  ovarian,  303 
Cystitis,  189 

FV ALAND'S  hematocrit,  73 

^     Dare's  hemoglobinometer,  36 

Degeneration,  endoglobular,  138 

Delafield's  hematoxylin,  69 

Delirium,  404 

Dementia,  403 

Dengue,  451 

Density  and  opacity  of  blood,  94 

Dermatitis  herpetiformis,  200 

Diabetes  mellitus,  309 

alkalinity,  309 

blood  plaques,  312 

Bremer's  test,  310 

diagnosis,  312 

erythrocytes,  311 

glycemia,  309 

hemoglobin,  31 1 

iodine  reaction,  312 

leucocytes,  312 

lipacidemia,  309 

lipemia,  309 


INDEX    OF     SUBJECTS. 


457 


Diabetes  mellitus,  specific  gravity,  312 

Williamson's  test,  309 
Diapedesis,  156 
Diaphragm,  ocular,  50 
Differential  counting,  70 

table  of  the  anemias,  243 
of  leukemia,  etc.,  275 
of    normoblasts    and    niegalo- 

blasts,  145 
of  the  leucocytes,  172 
of  the  malarial  parasites,  376 
Digestion  leucocytosis,  179 

m  diabetes  mellitus,  312 
in  gastric  carcinoma,  388 
in  gastric  ulcer,  345 
in  gastritis,  344 
in  infants,  281 
Diluting  fluids,  40 
Diphtheria,  312 
diagnosis,  316 

effects  of  antitoxin,  313,  314 
erythrocytes,  313 
hemoglobin,  312 
leucocytes,  313 
Disease,  malignant,  384 
Addison's,  299 
Barlow's,  349 
Banti's,  231 
Biermer's,  218 
Duhring's,  200 
Graves',  333 
Griesinger's,  357 
Hodgkin's,  267 
Laennec's,  351 
Potts' ,  440 
von  Jaksch's,  290 
Diseases,  hemorrhagic,  348 
Drug  eosinophilia,  201 
leucocytosis,  194 
lymphocytosis,  198 
Duodenal  ulcer,  346 
Durham's  hemocytometer,  52 
Dwarf  myelocytes,  171 
Dyes,  aniline,  59 
Dysentery,  316 

PCHINOCOCCUS,  392 
-'--'     Ectopic  pregnancy,  303 
Eczema,  200 
Effusion,  pericardial,  406 

peritoneal,  351 

pleural,  409 
Egyptian  chlorosis,  357 
Ehrlich's  hypothesis,  158 

triacid  stain,  64 
Ehrlich-Weigert  fluid,  86 
Eichhorst's  corpuscles,  137 
Electricity,  effect  on  blood,  18 1 
Elephantiasis  Arabum,  335 
Emphysema,  305 


Empyema,  410 

of  gall-bladder,  296 
Endocarditis,  malignant,  392 
Endoglobular  degeneration,  138 
Engel's  alkalimeter,  77 
Enteralgia,  303 
Enteric  fever,  317 

bacteriology,  317 
diagnosis,  331 
erythrocytes,  326 
hemoglobin,  326 
leucocytes,  328 
serum  test,  319 
spot  cultures,  318 
Enteritis,  316 
Eosin  and  hematoxylin  stain,  68 

and  methylene-blue  stain,  67 
Eosinophile  granules,  157 
Eosinophiles,  165 

diminution  in,  after  castration,  201 
after  hemorrhage,  201 
during  digestion,  201 
in  acute  febrile  diseases,  201 
in  carcinoma,  389 
in  chlorosis,  215 
in  diphtheria,  315 
in  enteric  fever,  330 
in  erysipelas,  333 
in  gastric  ulcer,  346 
in  Hodgkin's  disease,  269 
in  lymphatic  leukemia,  260 
in  malarial  fever,  383 
in  measles,  396 
in  meningitis,  397 
in  pernicious  anemia,  228 
in  pertussis,  409 
in  pneumonia,  415 
in  sarcoma,  390 
in  varicella,  448 
terminal,  201 
Eosinophilia,  198 
after  coitus,  199 
after  splenectomy,  274 
definition,  198 
during  menstniation,  199 
experimental,  201 
factors,  199 

in  ankylostomiasis,  357 
in  asthma,  306 
in  diseases  of  the  bones,  200 
of  the  sexual  organs,  201 
of  the  sympathetic  nervous  sys- 
tem, 201 
in  gonorrhea,  346 
in  helminthiasis,  200 
in  hemorrhagic  effusions,  409 
in  herpes  zoster,  353 
in  infancy,  199 
in  osteosarcoma,  390 
in  oxyuris  vermicularis  infection,  357 


458 


INDEX     OF     SUBJECTS. 


Eosinophilia  in  rheumatic  fever,  423 
in  scarlet  fever,  426 
in  septicemia,  431 
in  skin  diseases,  200 
in  spleno-medullarj'  leukemia,  255 
in  starvation,  201 
in  syphilis,  434 
in  splenic  tumors,  200 
in    tenia    mediocanellata    infection, 

357 

in  trichiniasis,  435 

in  the  xanthin  diathesis,  201 

physiological,  199 

post-febrile,  200 
Eosinophilic  myelocytes,  168 
Epilepsy,  405 
Erysipelas,  332 
Erythroblasts,  1 41 

atypical  forms,  146 

differential  count  of,  71 
Erythrocytes,  126 

after  fasting,  132 

ameboid  motility,  134 

appearance  in  fresh  blood,  126 

atypical  staining,  140 

averages  in  anemia,  148 

color,  126 

counting  the,  45,  54,  55 

crenation,  126 

deformities  of  size  and  shape,  1 36 

destruction,  128 

development,  128 

endoglobular  degeneration,  1 38 

granular  basophilia,  147 

histological  structure,  127 

hyperviscosity,  136 

influence  of  age  and  sex,  130 

of  constitution  and  nutrition,  132 
of  digestion,  133 
of  fatigue,  132 
of  high  altitudes,  133 
of  physical  factors,  130 
of  pregnancy,  menstruation  and 
lactation,  131 

isotbnicity,  135 

methods  of  counting,  40 

monochromatophilia,  140 

necrosis,  139 

normal  number,  129 

nucleation,  14 1 

origin  and  life  history,  128 

oval -shaped,  138 

pathological  changes,  134 

physiological  changes,  130 

polychromatophilia,  140 

rouleaux  formation,  126 

size,  129 

stroma,  127 

volume,  130 
Erythrocytometcr,  42 


Er\'thropyknosis,  372 
Estimation  of  alkalinity,  77 
of  coagulation  time,  79 

glass  slide  method,  80 
Wright's  method,  80 
of  specific  gravity,  75 
Ether  leucocytosis,  193 

narcosis,  416 
Examination  of  the  stained  specimen,  58 

unstained  specimen,  22 
Experimental  eosinophilia,  201 

leucocytosis,  193 
Extractives  of  blood,  94 

"CAT  in  the  blood,  106 

-*-  tests  for,  107 

Fatty  acids  in  the  blood,  no 

test  for,  110 
Felon,  189 
Fetal  blood,  279 
Fever,  effect  on  blood,  333 

enteric,  317 

gastric,  343 

malarial,  359 

Malta,  394 

relapsing,  418 

rheumatic,  421 

scarlet,  423 

thermic,  355 

typhus,  444 

yellon',  449 
Fibrin,  100 

in  abscess,  295 

in  acromegaly,  298 

in  carcinoma,  384 

in  chlorosis,  209 

in  cholelithiasis,  308 

in  erysipelas,  332 

in  fever,  334 

in  gout,  347 

in  influenza,  355 

in  lymphatic  leukemia,  256 

in  measles,  395 

in  nephritis,  399 

in  pernicious  anemia,  219 

in  pneumonia,  41 1 

in  rheumatic  fever,  421 

in  sarcoma,  389 

in  scarlet  fever,  423 

in  sepsis,  427 

in  spleno-medullary  leukemia.  247 

in  variola,  448 

in  yellow  fever,  449 

pathological  variations,  102 

relation  to  leucocytosis.  103 
Filariasis,  334 

diagnosis,  342 

erythrocytes,  34I 

filaria  nocturna,  335 

hemoglobin.  34I 


INDEX    OF    SUBJECTS. 


459 


Filariasis,  leucocytes,  342 

occurrence,  334 

parasitology,  335 
Films,  preparing  the,  59 

staining  the,  63 
Fixation  methods,  61 

heat,  61 

chemical,  62 
Floating  kidney,  303 
Fluids,  diluting,  40 
Formalin  fixation,  62 
Fractures,  343 
Fresh  blood,  microscopical  examination 

of,  22 
Functional  neuroses,  402 
Furuncle,  189 

GALL-STONE,  308 
Gangrene,  189 

appendicular,  301 
Garrod's  thread  test,  109 
Gastrectasis,  344 
Gases  of  blood,  94 
Gastric  carcinoma,  386 

neurasthenia,  344 

tubules,  atrophy  of,  343 

ulcer,  345 
Gastritis,  343 
Gastro-enteritis,  316 
Genito-urinary  tuberculosis,  440 
German  measles,  396 
Glanders,  346 
Globulin,  119 
Glycemia,  108 

in  diabetes  mellitus,  309 

in  carcinoma,  385 
Goldhorn's  stain,  69 
Gonorrhea,  346 

Gout,  347 

Gower's  hemocytometer,  54 
hemoglobinometer,  34 

Granular  basophilia,  147 

in  carcinoma,  3S7 
in  lead  poisoning,  417 
in  malarial  fever,  38 1 
in  pernicious  anemia,  226 
in  secondary  anemia,  238 
in   spleno-medullary   leukemia, 
250 

Granules,  leucocyte,  157 

Graves'  disease,  333 

Grippe,  354 

Guaiacol  poisoning,  416 

Gunther's  method  of  staining  bacteria,  86 

HALITUS  of  blood,  95 
Hammerschlag's  method,  75 
Hayem's  achromacyies,  138 
pseudo-bacilli,  138 
solution,  41 


Heat  exhaustion,  355 

fixation,  61 
Heart,  chronic  valvular  disease,  446 
dilatation  of,  406 
ulcerative  endocarditis,  392 
Helminthiasis,  intestinal,  356 
Helminthoma  elastica,  342 
Hemameba  leukemi^e,  245 

malariae,  359 
Hematin,  119 
Hematocrit,  Daland's,  73 
Hematoidin,  120 
Hematoporphyrin,  120 
Hemin,  120 
Hemochromogen,  119 
Hemoconia,  151 
Hemocytolysis,  115,  128 
in  fever,  333 

in  guaiacol  poisoning,  416 
in  insolation,  355 
in  malarial  fever,  380 
in  pyrodin  poisoning,  417 
in  yellow  fever,  450 
Hemocytometer,  Durham's,  52 
Gower's,  54 
Oliver's,  56 
Thoma-Zeiss,  42 
Hemogenesis,  128 
adult,  143 
deficient,  115 
embryonal,  144 
Hemoglobin,  119 

absolute  amount,  1 22 

after  anesthesia,  416 

averages  in  anemia,  121 

chemistry  of,  1 19 

estimation  of,  25,  32,  34,  36,  39,  96 

in  menstruation,  121 

influence  of  arsenic  on,  121 

of  iron  on,  120 
origin,  120 
reduced,  119 

tests  in  surgical  operations,  1 21 
Hemoglobinemia,  123 
from  burns,  124 
from  drugs,  123 
from  exposures  to  cold,  124 
from  heterogeneous  blood,  124 
from  mushroom  poisoning,  124 
from  snake  and  scorpion  venom,  417 
in  acute  yellow  atrophy  of  the  liver, 

298 
in  enteric  fever,  124 
in  epidemic  hemoglobinuria,  124 
in  insolation,  355 
in  malarial  fever,  380 
in  paroxysmal  hemoglobinuria,  124 
in  Raynaud's  disease,  124 
in  scarlet  fever,  424 
in  scurvy,  124 


460 


INDEX    OF     SUBJECTS. 


Hemoglobinemia  in  septicemia,  430 
in  syphilis,  433 
in  typhus  fever,  444 
in  variola,  448 
in  yellow  fever,  450 
spectrum  of,  125 
test  for,  124 
Hemoglobinometer,  Dare's,  36 
Gowers',  34 
Oliver's,  32 
Tallquist's,  39 
Hemometer,  von  Fleischl's,  25 
Hemophilia,  348 
Hemophilics,  danger  of  hemorrhage  in, 

21 
Hemorrhage,  efifect  on  blood,  240 
regeneration  after,  241 
treatment  by  saline  transfusion,  241 
Hemorrhagic  diseases,  348 
Hepatic  abscess,  296 
carcinoma,  388 
cirrhosis,  350 
colic,  309 
Herpes  zoster,  353 
Hewes's  stain,  65 
Hodgkin's  disease,  267 
alkalinity,  267 

appearance  of  fresh  blood,  267 
basophiles,  269 
blood  plaques,  269 
coagulation,  267 
color  index,  267 
deformed  erythrocytes,  267 
diagnosis,  269 
eosinophiles,  269 
erylhroblasts,  267 
erythrocytes,  267 
hemoglobin,  267 
leucocytes,  268 
mast  cells,  269 
myelocytes,  269 
polychromatophilia,  267 
relative  lymphocytosis,  268 
specific  gravity,  267 
symptoms,  270 
Hydremia,  105 
in  fever,  334 
in  nephritis,  399 
in  valvular  heart  disease,  446 
Hydrocyanic  acid  poisoning,  417 
Hydrophobia,  417 
Hyperchlorhydria,  344 
Hyperinosis,  102 
Hyperleucocytosis,  185 
Hypertonicity,  135 
Hypertrophic  hepatic  cirrhosis,  351 
Hyperviscosity.  136 
Hypochlorhydria,  344 
Hypochondriasis,  402 
Hypoleucocytosis,  185 


Hypothesis,  Ehrlich's,  15S 
Hypotonicity,  135 
Hypinosis,  102 
Hysteria,  402 

TCTERUS,  353 

A      Ileus,  357 

Illuminating  gas  poisoning,  192,  417 

Index,  color,  122 

volume,  75,  130 

Infected  wounds,  189 

Infection,  latent,  ill 

Influenza,  354 

Initial  feeding,  effect  on  blood,  281 

Insolation,  355 

Intestinal  helminthiasis,  356 
inflammation,  316 
obstruction,  357 

Iodine  poisoning,  417 

Iodine  reaction,  174 

in  abscess,  295 

in  anemia,  175 

in  diabetes  mellitus,  312 

in  pneumonia,  415 

in  puerperal  fever,  431 

in  purpura  hemorrhagica,  175 

in  septicemia,  431 

in  septic  tuberculosis,  441 

Iron,  efifect  on  hemoglobin,  120 
in  blood,  119 
in  eosinophiles,  158 

Irritants,  effect  on  blood,  194 

Ischemia,  1 13 

Ischio-rectal  abscess,  391 

Isotonicity,  135 

TOFFROY'S  sign,  217 
J      Jaundice,  353 
Tenner's  stain,  65 
Justus'  test,  433 

T^IDNEV,  carcinoma  of,  387 
J^     Kra-kra,  335 

T  ACTATION,  effect  on  blood,  181 

^     Laennec's  cirrhosis,  350 

Laked  blood,  94 

Large  mononuclear  leucocytes,  161 

Latent  infection,  iii 

Lead  poisoning,  417 

Leprosy,  358 

Leptomeningitis,  396 

Leucocytes,  155 

ameboid  properties,  156 

appearance  in  fresh  blood,  155 

classification,  159 

counting  the,  49,  53,  55 

differential  count  of,  70 
table  of,  172 

fatty  degeneration,  451 


INDEX     OF     SUBJECTS. 


461 


Leucocytes,  fractured,  24 

granules,  157 

iodine  reaction,  174 

methods  of  counting,  40 

nonnal  percentages  in  adults,  159 
in  children,  282 
number  in  adults,  159 
in  children,  281 

origin  and  development,  173 

perinuclear  basophilia,  176 

phagocytes,  156 

pigmented,  24,  355,  375,  420 

size,  155 

vacuolated,  24 

varieties,  159 
Leucocytic  phase,  186 
Leucocytolysis,  186 
Leucocytometer,  42 
Leucocytosis,  176 

after  thymectomy,  196 

after  splenectomy,  272 

average  increase,  183 

definition,  176 

differential  changes,  183 

digestion,  179 

drug,  194 

ether,  193 

experimental,  193 

factors,  178,  184 

from  mechanical  and  thermal  influ- 
ences, i8i 

functions,  184 

general,  185 

in  general  infectious  diseases,  189 

in  malignant  disease,  190 

in  simple  and  infective  local  inflam- 
mations, 189 

inflammatory  and  infectious,  187 

influence  of  chemotaxis,  184 

leucocytic  phase,  186 

leucopenic  phase,  186 

local,  185 

marrow  changes,  187 

of  pregnancy  and  parturition,  180 

of  the  new-born,  178 

pathological,  182 

physiological,  177 

post-hemorrhagic,  19 1 

terminal,  181 

toxic,  192 

traumatic,  185 
Leucopenia,  203 

experimental,  206 

in  chlorosis,  215 

in  diphtheria,  314 

in  enteric  fever,  328 

in  gastritis,  344 

in  gastro- enteritis  of  infancy,  205 

in  Hodgkin's  disease,  269 

in  malarial  fever,  382 


Leucopenia  in  measles,  395 
in  peritonitis,  408 
in  pernicious  anemia,  227 
in  pneumonia,  414 
in  sepsis,  431 
in  splenic  anemia,  233 
in  tuberculous  abscess,  443 
in  typhus  fever,  444 
pathological,  205 
physiological,  204 
Leucopenic  phase,  186 
Leukemia,  244 
acute,  260 

blood  picture,  261 

clinical  features,  260 

duration,  261 

in  children,  285 

statistics,  261 

transition   from   chronic    forms, 
261 
frequency  of  difi"erent  forms,  244 
in  children,  284 
influence  of   intercurrent  infections, 

261 
lymphatic,  256 

alkalinity,  256 

appearance  of  fresh  blood,  256 

atypical  lymphocytes,  259 

atypically  stained  erythrocytes, 
258 

basophiles,  260 

blood  plaques,  260 

coagulation,  256 

color  index,  257 

deformed  erythrocytes,  258 

diagnosis,  264 

eosinophiles,  260 

erythroblasts,  257 

erythrocytes,  257 

hemoglobin,  257 

leucocytes,  258 

leukoblasts,  259 

lymphocytosis,  259 

lymphogonien,  259 

mast  cells,  260 

myelocytes,  260 

polynuclear  neutrophiles,  260 

specific  gravity,  256 
parasitology,  244 
spleno-medullary,  246 

alkalinity,  247 

appearance  of  fresh  blood,  246 

atypical  myelocytes,  253 

polynuclear     neutrophiles, 

253 
basophiles,  256 
blood  plaques,  256 
Charcot-Leyden  crystals,  246 
coagulation,  247 
color  index,  248 


462 


INDEX    OF     SUBJECTS. 


Leukemia,    spleno-medullary,    deformed 
erythrocytes,  250 
degenerate  forms  of  leucocytes, 

.254 
diagnosis,  263 
dwarf  myelocytes,  252 
eosinophilia,  255 
eosinophilic  myelocytes,  255 
erythroblasts,  248 
erythrocytes,  247 
fibrin,  247 

fluctuations  in  hemoglobin  and 
erythrocytes,   248 
in  number  of  leucocytes,  25 1 
fractured  leucocytes,  254 
granular  basophilia,  250 
hemoglobin,  247 
influence  of  arsenic,  251 
karyokinesis,  250 
leucocytes,   250, 
lymphocytes,  255 
mast  cells,  256 
megaloblasts,  249 
myelocytes,  252 
nuclear  extrusion,  250 
polychromatophilia,   250 
polynuclear  neutrophiles,  253 
predominance    of    normoblasts, 

249 
pyknosis,  250 

relation  of  erythrocyte  and  leu- 
cocyte counts,  248 
remissions,  251 
specific  gravity,  247 
stimulation  forms,  255 
splenectomy  in,  274 
transformation    into  pernicious  ane- 
mia, 284 
transformations  of  type,  261 
Leukoblasts,  259 
Light-proof  hemometer  box,  30 
Lipacidemia,  no 

in  acute  yellow  atrophy  of  the  liver, 

298 
in  diabetes  mellitus,  309 
Lipemia,  106 

in  diabetes  mellitus,  309 
in  fractures,  343 
Liquor  sanguinis,  93 
Liver,  abcess,  296 

acute  yellow  atrophy,  298 
carcinoma,  388 
cirrhosis,  350 
Lowenthal's  reaction,  420 
LQwit's  ameba,  245 
Lungs,  malignant  neoplasms  of,  4II 
Lupus,  200 
Lymph  scrotum,  335 
Lymphangitis,  335 
Lymphemia,  261 


Lymphocytes,  small,  160 

large,  161 
Lymphocytosis,  196 

absolute,  196 

after  splenectomy,  274 

cachectic,  197 

definition,  196 

differential  changes,  196 

drug,  198 

factors,  197 

in  acromegaly,  298 

in  acute  infections,  197 

in  Addison's  disease,  299 

in  adenitis,  197 

in  carcinoma,  389 

in  children,  2S2 

in  chlorosis,  215 

in  convulsions,  404 

in  diphtheria,  315 

in  enteric  fever,  330 

in  exophthalmic  goitre,  ^^^ 

in  filariasis,  342 

in  gastritis,  344 

in  gastro-enteritis,  289 

in  Hodgkin's  disease,   269 

in  lymphatic  leukemia,  259 

in  malarial  fever,  383 

in  malignant  disease,  389,  390 

in  Malta  fever,  394 

in  measles,  396 

in  meningitis,  397 

in  osteomalacia,  406 

in  pernicious  anemia,  227 

in  pertussis,  409 

in  pneumonia,  415 

in  purpura,  350 

in  rachitis,  289 

in  sarcoma,  390 

in  scarlet  fever,  426 

in  scurvy,  350 

in  secondary  anemia,  197 

in  splenic  anemia,  238 
tumors,  197 

in  syphilis,  434 

in  thyroid  tumors,  198 

in  tuberculosis,  441 

in  variola,  449 

of  infancy,  197 

post-hemorrhagic,  192 

relative,  196 

terminal,  197 
Lymphogonien,  259 

TUTACROCVTES,  136 
^^^      Making  the  puncture,  19 
Malarial  cachexia,  383 
fever,  359 

anemia,  381 
blood  plaques,  384 
diagnosis,  384 


INDEX    OF     SUBJECTS. 


463 


Malarial  fever,  erythrocytes,  379 

hemoglobin,  379 

leucocytes,  382 

parasite,  359 

crescentic  forms,  373 
degenerate  forms,  367, 

370,  374 
development  in  inan,  359 

in  mosquito,  360 
disc  forms,  371 
estivo-autumnal,  370 
flagellate  foiTOS,  366,  370, 

374 
infection      with      multiple 

groups,   361,  367 
intracellular  hyaline  forms, 

362,  368,  371 
ovoid  bodies,  373 
pigmented  extracellular 

forms,  365,  370,374 
intracellular        forms, 

363.  368,  372 
leucocytes,  375 
quartan,  367 
ring  forms,  371 
segmenting      forms,     364, 

369.  372 
spherical  bodies.  373 
tertian,  362 
vacuolized  forms,  367,  370, 

375 
phagocytosis,  375 
technique    of  examination,  376 
spleen,  274 
Male  chlorosis,  217 
Malignant  disease,  384 

endocarditis,  392 
Malta  fever,  394 
Mania,  403 

Maragliano's  necrosis,  139 
Massage,  effect  on  blood,  181 
Mast  cell  granules,  157 
cells,  168 

in  Asiatic  cholera,  305 

in  carcinoma,  202 

in  chlorosis,  202 

in  filariasis,  342 

in  gonorrhea,  202 

in  lymphatic  leukemia,  260 

in  mycosis  fungoides,  202 

in  septic  bone  disease,  202 

in  skin  diseases,  202 

in  splenic  anemia,  233 

in   spleno-meduUary   leukemia, 

256 
in  trichiniasis,  436 
Mastitis,  189 
Masturbation,  403 
Measles,  395 
Megaloblastic  blood  picture,  229 


Megaloblasts,  143 
Megalocytes,  136 
Melancholia,  403 
Melanemia,  107 

in  Addison's  disease,  299 
in  insolation,  355 
in  malarial  fever,  375 
in  relapsing  fever,  420 
Meningitis,  396 

cerebro-spinal,  397 
tuberculous,  397 
Mental  diseases,  402 
Mercury,  effect  on  blood,  432 
Mesoblasts,  146 
Methemoglobin,  1 19 
spectrum  of,  125 
tests  for,  124 
Methemoglobinemia,  124 
from  drugs,  1 24 
in  Addison's  disease,  299 
in  poisoning,  416 
in  purpura  hemorrhagica,  348 
Methods,  fixation,  61 
of  examination,  I9 
of  staining,  63 
Microblasts,  145 
Microcytes,  137 

Microspectroscope,  Sorby-Beck,  81 
Miculicz's  dictum,  121 
Mitral  lesions,  447 
Monochromatophilia,  140 
Mononuclear  neutrophiles,  171 
Mosquito,  development  of  filaria  nocturna 

in,  337 
of  malarial  parasite  in,  360 
yellow^  fever,  450 
Mucinoblasts,  170 
Multiple  neuritis,  402 
Muscular  exercise,  effect  on  blood,  i8l 
Myelemia,  202 
Myelocytes,  167 

atypical  forms  in  leukemia,  253 

dwarf,  171 

eosinophilic,  168 

in  abscess,  297 

in  Addison's  disease,  299 

in  anemia  of  children,  283 

infantum  pseudo-leukemica,  290 

in  carcinoma,  389 

in  chlorosis,  215 

in  convulsions,  404 

in  diphtheria,  316 

in  enteric  fever,  331 

in  erysipelas,  333 

in  gastro- enteritis,  289 

in  gout,  347 

in  herpes  zoster,  353 

in  Hodgkin's  disease,  269 

in  infantile  enteric  fever,  289 
syphilis,  288 


464 


INDEX     OF     SUBJECTS. 


Myelocytes  in  lymphatic  leukemia,  260 

in  malarial  fever,  383 

in  myxedema,  398 

in  osteomalacia,  406 

in  pernicious  anemia,  228 

in  post-hemorrhagic  leucocytosis,  192 

in  rachitis,  288 

in  sarcoma,  391 

in  scarlet  fever,  426 

in  secondary  anemia,  238 

in  splenic  anemia,  233 

in  spleno-medullary  leukemia,  252 

in  syphilis,  434 

in  tuberculosis,  441 

in  variola,  449 

in  yellow  fever,  451 
Myxedema,  398 

MECROSIS,  Maragliano's,  139 
■*-^      Needle  for  blood  culturing,  84 
Negro  lethargy,  335 
Nephritis,  399 
Nervous  diseases,  402 
Neuralgia,  402 

ovarian,  304 
Neurasthenia,  402 

gastric,  344 

sexual,  403 
Neuritis,  402 
Neuroses,  functional,  402 
Neutral  dyes,  59 
Neutrophile  granules,  157 
Neutrophiles,  polynuclear,  163 

mononuclear,  171 
Neutrophilic  pseudo-lymphocytes,  171 
Newton's  rings,  47 
Nikiforoff's  method  of  fixation,  62 
Nitrobenzol  poisoning,  417 
Nitroglycerine  poisoning,  417 
Normoblasts,  141 
Nuclear  stains,  59 
Nucleated  erythrocytes,  141 
Nucleolation  of  lymphocytes,  260 

rjBERMEIER'S  spirillum,  418 
^     Obesity,  406 
Objects  of  staining,  58 
Obstruction,  intestinal,  357 
Obstructive  jaundice,  coagulation  in,  353 
Ocular  diaphragm,  50 
Odor  and  viscosity  of  blood,  95 
Oligemia,  103 
Oligochromemia,  121 
Oligocythemia,   148 
Oliver's  hemocytometer,  56 
hemoglobinometer,  32 
Opium  poisoning,  417 
Osmic  acid  fixation,  63 
Osteomalacia,  406 
Osteomyelitis,  427 


Osteomyelitis,  tuberculous,  440 
Osteosarcoma,  390 
Otitis  media,  189 
Oval-shaped    erj'throcytes,  138 

in  epidemic  dropsy,  223 

in  pernicious  anemia,  223 

in  purpura  hemorrhagica,  223 
Ovarian  abscess,  296 

cyst,  303 
Ovaritis,  189 
Oven  for  fixation,  61 
Oxyhemoglobin,  119 

spectrum  of,  125 

PACHYMENINGITIS,  396 

'^       Palmar  abscess,  296 

Pancreatitis,  189 

Panoptic  staining,  63 

Paresis,  403 

Pathological  leucocytosis,  182 

leucopenia,  205 
Pellagra,  189 
Pelvic  abscess,  296 
Pemphigus,  189 
Pericardial  effusion,  406 
Perinuclear  basophilia,  176 
Peritonitis,  407 

appendicular,  301 
hysterical,  408 
septic,  407 
serous,  407 
tuberculous,  440 
Periurethral  abscess,  296 
Pernicious  anemia,  218 

alkalinity,  220 

appearance  of  fresh  blood,  218 

blood  plaques,  228 

coagulation,  219 

color  index,  220 

diagnosis,  228 

Eichhorst's  corpuscles.  223 

eosinophiles,  228 

erythroblasts,  223 

erythrocytes,  220 

fibrin,  219 

fluctuations  in  number  of  eryth- 
rocytes, 225 

granular  basophilia,  226 

hemoglobin,  220 

horseshoe-shaped  cells,  223 

in  children,  284 

isotonicity,  135 

leucocytes,  227 

megaloblasts,  224 

megalocytes,  223 

mesoblasts,  225 

microbla.sts,  225 

myelocytes,  228 

nuclear  extrusion,  225 

oligemia,  218 


INDEX    OF     SUBJECTS. 


465 


Pernicious  anemia,  oval-shaped  cells,  223 
phantom  corpuscles,  219 
poikilocytosis,  223 
polychromatophilia,  225 
polynuclear  neutrophiles,  227 
predominance  of  megaloblasts, 

224 
relative  lymphocytosis,  227 
rouleaux  formation,  219 
specific  gravity,  219 
symptoms,  229 
syphilitic,  432 

transformation    into    leukemia, 
284 
Pertussis,  408 
Pfeiflfer's  phenomenon,  87 
Phagocytosis,  156,  185 
in  malarial  fever,  375 
in  relapsing  fever,  420 
Phantom  corpuscles,  138 

tumor,  408 
Phlebitis,  189 
Phosphorus  poisoning,  417 
Physiological  leucocytosis,  177 

leucopenia,  204 
Pigmented  leucocytes,  in  insolation,  355 
in  malarial  fever,  375 
in  relapsing  fever,  420 
Pipette,  Durham's,  53 
Gower's,  35 
Oliver's,  32 
Thoma-Zeiss,  42 
Pinocytosis,  156 
Plague,  bubonic,  306 
Plasma  stains,  59 
Plasmodium  malarire,  359 
Plethora,  104 

in  obesity,  406 
Pleura,  malignant  neoplasms  of,  411 
Pleurisy,  serous,  409 

purulent,  410 
Plimmer's  bodies,  385 
Plumbic  neuritis,  402 
Plumbism,  acute,  417 
Pneumonia,  411 

artificial  leucocytosis,  414 
bacteriology,  411      . 
blood  plaques,  415 
diagnosis,  415 

effect  of  antipyretics  and  cold,  414 
erythrocytes,  412 
hemoglobin,  412 
hyperinosis,  411 
iodine  reaction,  415 
leucocytes,  413 
lymphocytosis,  415 
serum  test,  411 
specific  gravity,  411 
Poisoning,  416 
Poikilocytes,  137 

30 


Polychromatophilia,  140 
Polycythemia,  149 

after  paracentesis,  351 
after  transfusion,  242 
after  urinary  crises,  150 
after  use  of  purgatives,  316 
during  blood  regeneration,  242 
digestion,  132 
menstruation,  131 
from  admmistration  of  lymphogogues 

and  emetics,  150 
from  physiological  causes.  149 
in  acute  yellow  atrophy  of  the  liver, 

"298 
in  Asiatic  cholera,  304 
in  asthma,  305 
in  bubonic  plague,  307 
in  convulsions,  404 
in  diarrhea,  316 
in  dysentery,  316 
in  emphysema,  305 
in  fever,  333 

in  gastric  and  esophageal  cancer,  350 
carcinoma,  386 
ulcer,  345 
in  gastritis,  343 
in  icterus,  354 

in  illuminating-gas  poisoning,  417 
in  insolation,  355 
in  nephritis,  401 
in  phosphorus  poisoning,  417 
in  pneumonia,  412 
in  the  new-born,  130 
in  tuberculosis,  440 
in  valvular  heart  disease,  447 
of  high  altitudes,  133 
Polyemia,  104 

Polynuclear  neutrophiles,  163 
Post-hemorrhagic  anemia,  239 
blood  crises,  242 
plaques,  241 
color  index,  242 
erythroblasts,  242 
erythrocytes,  240 
etiology,  239 
fatality,  240 
hemoglobin,  240 
hydropic  erythrocytes,  242 
immediate  effects  of  blood  loss, 

240 
leucocytes,  240 
leucocytosis,  191 
lymphocytosis,  192 
microcytes,  242 
oligemia,  240 
polycythemia,  242 
polychromatophilia,  242  ^ 
rapidity  of  hemoglobin  gain,  242 
regeneration,  241 
saline  solution,  effect  of,  241 


466 


INDEX     OF     SUBJECTS. 


Potts'  disease,  440 
Ponfick's  corpuscles,  13S 
Pre-agonal  leucocytosis,  iSi 
Pregnancy,  131 

ectopic,  303 
Preparing  the  films,  59 

the  slide,  21 
Prince's  stain,  66 
Protozoa  in  beri-beri,  402 

in  carcinoma,  3S5 

in  leukemia,  245 

in  measles,  395 

in  variola,  448 
Prurigo,  200  • 

Pseudo-anemia,  1 13 
Pseudo-bacilli,  138 
Pseudolymphocyles,  neutrophilic,  171 
Psoriasis,  200 
Ptomaine  poisoning,  417 
Puerperal  fever,  430 
Purges,  effects  on  blood,  316 
Purpura,  34S 
Purulent  lesions,  189 
Pyelonephritis,  1 89 
Pyemia,  427 
Pyknosis,  250 
Pyonephrosis,  303 
Pyosalpinx,  296 
Pyrodin  poisoning,  417 
Pyrogallic  acid  poisoning,  417 
Pyrogallol  poisoning,  417 

/QUANTITY  of  blood,  93 
>C     Quinsy,  435 
Quotient,  blood,  122 

RABIES,  417 
Raspberry -jelly  clots,  247 
Ratio  of  erythrocytes  to  leucocytes,  155 

of  erythrocytes  to  plaques,  72 
Reaction,  Arloing  and  Courmont's,  437 
Bordefs,  88 
Lowenthal's,  420 
Widal's,  86 

of"  blood,  95 

pathological  variations,  97 
physiological  variaiions,  96 
Rectum,  carcinoma  of,  388 
Reizungsformen,  1 71 
Relapsing  fever,  418 
bacilli,  419 
diagnosis,  421 
diplococci,  419 
erythrocytes,  421 
hemoglobin,  421 
leucocytes,  421 
Lowenthal's  reaction,  420 
melanin,  420 
parasitology-,  418 
phagocytosis,  420 


Relapsing   fever,  pigmented   leucocytes, 

420 
Remissions  in  pernicious  anemia,  225 

in  spleno-medullary  leukemia,  251 
Renal  abscess,  296 

colic,  309 
Revulsives,  effect  on  blood,  194 
Rheumatism,  chronic,  422 
Rheumatic  fever,  421 

alkalinity,  421 

bacteriology,  422 

coagulation,  421 

color  index,  422 

diagnosis,  423 

er}-throcytes,  422 

fibrin,  421 

hemoglobin,  422 

leucocytes,  422 
Rollet,  stroma  of,  127 
Rotheln,  396 
Rouleaux  formation,  126 
Rupture  of  the  spleen,  274 
Russell's  bodies,  385 

SALINE  purges,  effect  on  blood,  316 
Salts  of  blood,  93 
Sanarelli's  bacillus,  450 
Sapremia,  427 
Sarcoma,  3S9 

coagulation,  389 
deformed  er}throcytes,  390 
diagnosis,  391 
erythroblasts,  390 
erythrocytes,  389 
fibrin,  3S9 
hemoglobin,  389 
leucocytes,  390 
specific  gravity,  389 
Scarlet  fever,  423 

bacteriolog}',  424 
blood  plaques,  426 
coagulation,  423 
diagnosis,  426 
erythrocytes,  424 
fibrin,  423 
hemoglobin,  424 
leucocytes,  425 
specific  gravity,  423 
Scleroderma,  200 
Scorpion  poisoning,  417 
Scrotum,  lymph,  335 
Scurvy,  348 
Secondary  anemia,  236 
alkalinity,  237 

appearance  of  fresh  blood,  236 
,,-^.  average  hemoglobin  and  eryth- 

rocyte losses,  23S 
blood  plaques,  239 
coagulation,  236 
color  index,  237 


INDEX    OF     SUBJECTS. 


467 


Secondary  anemia, deformed  erythrocytes, 
238 
diagnosis,  239 
eosinophiles,  238 
erythroblasts,  238 
erythrocytes,  237 
granular  basophilia,  238 
hemoglobin,  237 
leucocytes,  238 
myelocytes,  238 
pallor  of  erythrocytes,  238 
poikilocytosis,  238 
polychromatophilia,  238 
polynuclear  neutrophiles,  238 
relative  lymphocytosis,  238 
specific  gravity,  236 
Septic  arthritis,  427 
Septicemia  and  pyemia,  427 
bacteriology,  428 
color  index ,  430 
diagnosis,  431 
erythrocytes,  429 
fibrin,  427 
hemoglobin,  429 
leucocytes,  431 
serum  reaction,  427 
Serous  plethora,  104 
Serum  reaction,  determination  of,  86 
in  Asiatic  cholera,  304 
in  bubonic  plague,  307 
in  children,  290 
in  colon  infections,  427 
in  enteric  fever,  319 
in  leprosy,  358 
in  Malta  fever,  394 
in  pneumococcus  infections,  427 
in  pneumonia,  41 1 
in  relapsing  fever,  420 
in  septicemia,  427 
in  streptococcus  infections,  427 
in  tuberculosis,  437 
in  yellow  fever,  450 
Sexual  neurasthenia,  403 
Shadow  corpuscles,  138 
Sherrington's  solution,  41 
Shingles,  353 
Sign,  Joffroy's,  217 
Sleeping  sickness,  335 
Slide,  preparing  the,  21 
Small  lymphocytes,  160 
Small -pox,  448 
Sodium  nitrite  poisoning,  417 
Solution,  Hayem's,  41 
isotonic,  135 

saline,  after  hemorrhage,  241 
Sherrington's,  41 
Toisson's,  41 
Sorby-Beck  microspectroscope,  81 
Sorby's  tubular  cell,  82 
Specific  gravity,  98 


Specific  gravity,  estimation  of,  75 
in  Asiatic  cholera,  304 
in  carcinoma,  385 
in  children,  280 
in  chlorosis,  209 
in  diabetes  mellitus,  312 
in  Hodgkin's  disease,  267 
in  icterus,  353 
in  lymphatic  leukemia,  256 
in  nephritis,  399 
in  pernicious  anemia,  219 
in  pneumonia,  411 
in  purpura  hemorrhagica,  348 
in  sarcoma,  389 
in  scarlet  fever,  423 
in  secondary  anemia,  236 
in   spleno-medullary   leukemia, 

247 
in  the  fetus,  279 
in  the  new-born,  280 
in  valvular  heart  disease,  446 
normal  range,  98 
pathological  variations,  99 
relation  to  hemoglobin,  100 
table    of    hemoglobin     equiva- 
lents, lOI 
Spectra,  blood,  125 
Spectroscopical  examination,  81 
Spirillum  of  Obermeier,  418 
Splenectomy,  272 
Splenic  anemia,  231 

appearance  of  fresh  blood,  231 
blood  plaques,  233 
color  index,  232 
diagnosis,  233 
eosinophiles,  233 
erythroblasts,  232 
erythrocytes,  231 
hemoglobin,  231 
leucocytes,  233 
mast  cells,  233 
megaloblasts,  232 
megalocytosis,  232 
myelocytes,  233 
poikilocytosis.  232 
polychromatophilia,  232 
polynuclear  neutrophiles,  233 
relative  lymphocytosis,  233 
symptoms,  234 
Splenitis,  189 
Splenolymph  glands,  128 
Spot  culturing,  318 
Snake  poisoning,  417 
Stain,  Ehrlich's  triacid,  64 
Ehrlich-Weigert,  86 
eosin  and  hematoxylin,  68 

methylene-blue,  67 
Goldberger  and  Weiss' ,  1 74 
Hewes',  65 
Jenner's,  65 


468 


INDEX    OF     SUBJECTS. 


Stain,  Loffler's,  65 
Prince's,  66 

polychrome  methylene-blue,  69 
thionin,  69 
Stained  specimen,  examination  of  the,  58 
Staining,  methods  of,  63 
double,  63 
objects  of,  58 
panoptic,  63 
triple,  63 
Stasis,  effect  on  blood,  446 
Stegomyia  fasciata,  450 
Stimulation  forms,  171 

in   spleno-medullary   leukemia, 

255 
in  enteric  fever,  331 
in  erysipelas,  ^^3 
Stomach,  carcinoma  of,  388 
Stroma  of  Rollet,  127 
Sugar  in  the  blood,  108 

in  carcinoma,  385 
in  diabetes  mellitus,  309 
test  for,  108 
Sunstroke,  355 

Sweating,  effects  on  blood,  150 
Syphilis-,  432 

diagnosis,  434 
effect  of  mercury,  432 
erythrocytes,  432 
hemoglobin,  432 
Justus'  test,  433 
leucocytes,  434 

'T'ALLQUIST'S  hemoglobinometer,  39 
■■•      Tansy  poisoning,  417 
Teichmann's  crystals,  120 
Terminal  leucocytosis,  181 
Test,  Bordet's,  88 

Bremer's,  310 

for  acetone,  no 

for  alkalinity,  77 

for  bile,  1 10 

for  carbon    monoxide    hemoglobin, 
126 

for  fat,  107 

for  fatty  acids,  no 

for  glycogen,  174 

for  hemin,  120 

for  hemoglobin,  25 

for  hemoglohinemia,  124 

for  human  blood,  88 

for  methemoglobin,  124 

for  sugar,  108 

for  uric  acid,  109 

Garrod's,  109 

Justus',  433 

Lowenthal's,  420 

Widal's,  86 

Williamson's,  309 
Tetanus,  434 


Tetany,  405 

Thionin  stain,  69 

Thoma-Zeiss  hemocytometer,  42 

Thymectomy,  leucocytosis  after,  196 

Toadstool  poisoning,  417 

Toisson's  solution,  41 

Toluene  poisoning,  417 

Tonsillitis,  434 

Total  necrosis,  139 

Toxic  leucocytosis,  192 

Transitional  forms,  162 

Triacid  stain,  64 

Triboulet's  diplococcus,  422 

Trichiniasis,  ^35 

Tropical  anemia,  114 

Tuberculosis,  437 

bacteriolog)',  437 

diagnosis,  443 

erythrocytes,  439 

forms  of  anemia,  437 

genito-urinary,  440,  443 

glandular,  440,  443 

hemoglobin,  439 

hip-joint,  440,  442 

iodine  reaction,  441 

leucocytes,  441 

meningeal,  397,  443 

osseous,  440,  442 

peritoneal,  440,  443 

pleural,  440,  443 

polycythemia,  440 

pulmonary-,  439,  441 

secondary  infections,  439,  441 

serum  reaction,  437 
"^  '   vertebral,  440,  442 
Tuberculous  meningitis,  397 
Tubular  cell,  Sorby's,  82 
Tumor,  brain,  402 

phantom,  408 
Turpentine  poisoning,  417 
Typhus  fever,  444 

TTLCER,  duodenal,  346 
^     gastric,  345 
Uremia,  401 
Uric  acid,  in  gout,  347 

test  for,  109 
Uricacidemia,  109 
Urinary  crises,  effect  on  blood,  150 
Urticaria,   200 
Uskow's  theory,  173 
Uterus,  carcinoma  of,  388 

yACC  I  NATION,  445 
•     Valeur  globulaire,  122 
Valvular  heart  disease,  440 
Varicella,  447 
Variola,  448 
Varioloid,  449 
Violet  of  Hoyer,  69 


INDEX    OF     SUBJECTS.  469' 

Volume  index,  75,  130  Williamson's  test,  309 

Vomiting,  efifect  on  blood,  150  Wright's  coagulometer,  80 
Von  Fleischl's  hemometer,  25 

Von  Jaksch's  anemia,  290  y^LLOW  fever,  449 

WANDERING  spleen,  274  yAPPERT  counting  chamber,  44 

Whooping-cough,  408  Lt 

Widal's  test,  86 


INDEX    OF  AUTHORS. 


ABBOTT,  325,359 
-*^     Achalme,   113,422 
Achard,  304 
Adami,  85,  iii 
Addison,  299 
Afanassiew,  113,  419 
Affleck,  402 
Agramonte,  450 
Aiello,  348 
Albutt,  217 
Aldridge,  395 
Altmann,  158 
Ames,  193 
Aoyoma,  307 
Aporti,  120 
Archinard,  450 
Arloing,  437,  438 
Arnold,  164 
Arsamaskoff,  395 
Ash  ford,  357 
Askanazy,  99,  356 
Atkinson,  436 
Auch6,  417 

r)ADUEL,  412 

■*-'     Baginsky,  286,  424 

Balfour,  113,  444 

Barker,  158 

Bastianelli,  359,  360 

Beck,  438 

Becker,  99,  415 

Becquerel,  106,  354 

B6hier,  241 

Benario,  62 

Benda,  259* 

Bendix,  438 

Bennett,  246 

Bensaude,  304 

Benzacon,  448 

Berend,  96 

Besredka,  195,  315 

Bettman,  347 

Bierfreund,  121,  242,  386 

Biernacki,  304 

Bignami,  359,  360,  371,  380,  381 

Billings,  306,  313,  314,  414,  445 

Birk,  196 

Bize,  314 

Bjorkman,  iSl 

I^lake,  343 

Blix,  72 


Bloodgood,  358 

Blumer,  299,  436 

Boeckman,  159 

Boeni,  196 

Bohland,  180,  195,  206 

Bojanus,  196 

Bordet,  87,  88 

Bouchut,  313 

Bradford,  261 

Bramwell,  211,  398 

Brandenberg,  96,  417 

Bremer,  310 

Brieger,  429 

Brouardel,  316,  448 

Brown,  199,  358,  433,  435,  436,  440,  442 

Bruce,  394 

Buard,  438 

Bucbner,  185,  196 

Burmin,  96,  210,  247 

Bunge,  120 

Burr,  405 

Burrows,  193,  404 

pABOT,  138,  182,  206,  211,  215,  244, 

^     248,  298,  306,  343,   388,  397,   398, 

401,  402,   408,   410,   414,   416,   422, 

433,  434,  436,  451 
Cadet,  132 
Canard,  96 

Canon,  199,  202,  308,  354,  429 
Cantani,  97,  304,  348 
Capps,  75,  130,  171,  193,  388,  403 
Carroll,  450 
Carter,  313,  314 
Cassel,  285,  286 
Castellani,  317 
Castellino,  139 
Celli,  359 
Chadboume,  193 
Charcot,  24 
Charles,  394 
Charon,  287 
Charrin,  87 
Chantemesse,  332 
Chenzinsky,  68 
Class,  113,  424 
Cohn,  232 
Cole,  317 
Combe,  395 
Councilman,  359 
Courmont,  417,  437,  438,  449 


INDEX    OF    AUTHORS. 


471 


Cox,  395 
Coyon,  422 
Craig,  113 
Crajkowski,  424 
Curschmann,  318 
Czerni6wski,  428 
Czerny,  273,  274 

DA  COSTA,  416 
Daland,  72 
Dale,  433 
Dane,  440,  442 
Dare,  36 
Dawson,  242 
De  Amicis,  408 
Decastelle,  204 
Delafield,  69 
Delbert,  244 
Delestre,  292 
Delezene,  206 
Denig^,  1 10 
Denys,  350 
De  Rienzi,  196,  353 
de  Saussure,  335 
Desevres,  97 
Determann,  71 
Diabella,  100 
Dinkelspiel,  88 
Dionisi,  379,  381 
Dock,  359 
D'Orlandi,  205 
Douglas,  388 
Drouin,  96,  97,  332 
Dubroisay,  313 
Dunn,  335 

Durham,  52,  87  • 

Duval,  346 

EBSTEIN,  261 
Egger,  133 

Ehrlich,  58,  59,  62,  63,  64,  68,  142,  145, 
148,  158,  171,  173,  176,  184,  187,  197, 
205,242,  341,  357,409,417 

Eichhorst,  137 

Eisenlohr,  262 

Engel,  77,  96,  147,  447 

Engle,  316 

Eubank,  242 

Ewing,  193,  314,  315,  413,  445 

PAJARDO,  402 

^      Felsenthal,  314,  425 

Fil6,  313 

Filetti,  359 

Fink,  306 

Finlay,  450 

Fischl,  281 

Fodor,  334 

Fraenkel,  261,  262 

Freudberg,  96 


Freund,  108 
Friedlander,  181 
Frolich,  408 
Fussell,  261 
Futcher,  69,  176,  361 

pABRITSCHEWSKY,  156,  185,  306. 

^     314 

Garrod,  109,  347 

Gaylord,  385 

Georgiewsky,  416 

Gilbert,  313,  314 

Goldberger,  174 

Goldhorn,  69 

Goldscheider,  185,  194 

Golgi,  359 

Gollasch,  199 

Gowers,  25,  34,  54 

Gradwohl,  424 

Graeber,  210 

Gram,  129 

Grassi,  359,  360 

Gratea,  287 

Grawitz,  134,   147,  159,  213,   247,   298, 

309,   316,  349,   351,  354,  392,   401, 

416,  4J7,  429,  446,  447 
Greene,  223,  319 
Greenough,  345 
Griesinger,  357 
Griiber,  87 
Guiteras,  335 
Gundobin,  178,  282 
Giinther,  86 
Gwyn,  318,  398,  436 

HAGEN,  274 
Hall,  242 
Halla,  159,  448 
Hamel,  148,  417 

Hammerschlag,  75,  99,  210,  280,  423 
Hand,  196 
Hankin,  158,  I96 
Hanot,  352 
Hardy,  155,  164 
Hare,  414 
Harris,  170 
Hartley,  274 
Hartmann,  272 
Hartung,  388 
Hay,  316 
Hay  craft,  77 
Hayek,  251 
Hayem,  41,   102,    128,    129,    131,    132, 

138,   159,   219,   228,   240,    280,    281, 

33^,  350,  387,  400,  416 
Head,  192 
Hedin,  72 
Heidenrich,  421 
Heim,  415 
Henry,  335,  386 


472 


INDEX    OF    AUTHORS. 


Hewes,  65 

Hewetson,  359 

Hibbard,  180 

Hills,  220 

Hirschlafi",  429 

Hirt,  195 

Hofbauer,  175 

Hoffman,  388,  389 

Holmes,  68,  441 

Holt,  285 

Hoppe-Seyler,  108,  126,  309 

Howard,  361,  436 

Hubbard,  343 

Hubner,  356 

Hutchinson,  421 

TMMERMAN,  240,  348 
^      Israel,  142 

JACOB,  185,  194 

J     James,  84, 31 1, 317, 392, 399,412,492 
Jacques,  424 
Jeffries,  96 
Jehle,  354,  424 
Jellinek,  119 
Jenner,  63,  64 
Johnston,  322 
Jones,  433,  451 
Jopson,  261 
Joslin,  345 
Justus,  433 

TZAMINER,  175 

•l^     Kanthack,  155,  158,  164,  196 

Kelsch,  244,  381,  382 

Kerr,  435,  436 

Kisch,  405 

Kitasato,  306 

Klein,  354 

Kline,  431 

Kobert,  417 

Koblanck,  204 

Kochetkoff,  425 

Koeppe,  133 

Kohn,  412 

Kolisch.  176 

Kolle,  87 

Kolliker,  I42 

Kormoczi,  262 

Kraepelin,  398 

Kraus,  77,  96,  98,  334,  392 

Krause,  318 

Krausman,  195 

Krauss,  428 

Kretz,  395 

Krokiewicz,  385,  388 

Kronig,  417 

Kuhlman,  405 

Kuhnau,  317,  354,  392,  428 

Kurloff,  274 


T  AACHE,  134,  241,  400 

^     Lambert,  355 

Landois,  77,  99 

Laptschinski,  421 

Latham,  286 

Laveran,  359 

Lazarus,  58,  341 

Lazear,  69,  392,  450 

Le  Breton,  398 

Lehmann,  96 

Lechtenstern,  311,  357,  406 

Lenoble,  219,  236 

Lupine,  96 

Lesieur,  417 

Letzerich,  348 

Levene,  355 

Levy,  347 

Lewaschew,  444 

Lichty,  99,  344 

Liebrich,  77 

Lindenthal,  145,  417 

Litten,  148 

Lloyd  Jones,  99,  209 

Loffler*  65 

Lothrop,  336,  341 

Lowenthal,  420 

Lowit,  186,  194,  244,  259,  344 

Lowy,  96,  185,  237,  334 

Luciani,  205 

Lussana,  356 

Luxemberg,  402 

Lyon,  192 

AJAcCALLUM,  367 

^^^     Mackenzie,  115 

Mackie,  426 

MacPhail,  403,  405 

Mannaberg,  359,  371 

Manson,  335,  337,  339,  341 

Maraghano,  139,  ^^3,  3^5 

Marchiafava,  359,  371,  380 

Mastin,  355 

Mathias,  353 

McCrae,  232,  251,  387,  388 

Mertins,  433 

Metchnikoff,  87,  156,  359 

Meunier,  352,  408 

Meyer,  195 

Mickulicz,  121 

Miescher,  30 

Mitchell,  181 

Mongour,  438 

Montagard,  449 

Monti,  284,  288 

Morse,  284,  285,  286,  290,' 313,  409 

Muir,  186,  349 

Muller,  151,  255,  262,  263,  286,  388,  416" 

Murray,  398 

Musser,  394 

My  a,  96 


INDEX    OF     AUTHORS. 


473 


VTETTER,  308 
^^      Neufeld,  318 
Neuman,  436 
Neumann,  142,  429 
Neusser,  176,  201,  406 
Nicholls,  151 
Nikiforoff,  62 
Nuttal,  88 

OBERMEIER,  418 
Oertel,  410.  44^ 
Ogata,  307 
Okladnych,  304 
Oliver,  25,  32,  41,   56,    106,   122,    130, 

133,  181 
Osier,  217,    232,    234,    271,    359,    376, 

387.  388 
Ostrovosky,  356 
<Uto,  242 

OACCHIONI,  408 
A       Page,  424 

Pallowski,  244 
Pappenheim,  142,  147 

Pee,  424,  435 

Peiper,  98,  99,  423 

Perry,  198 

Peter,  434 

Petrone,  loi 

Petruschky,  428 

Pfeiffer,  86,  103,  354,  448 

Pick,  448 

Pieraccini,  412 

Plehn,  68 

Plimmer,  385 

Poggi,  121 

Pohl,  195 

Pollman,  285 

Ponfick,  138 

Porter,  113,  444 

Pothier,  450,  451 

Pratt,  336,  341    . 

Prince,  66 

Putnam,  398 


Q 


UINCKE,  220 


l>  ABINOWITCH,  438 

^     Ranvier,  355 

Reed,  448,  450 

Rees,  307 

Reinert,  134,  333^  403 

Rey,  332 

Reyne,  132 

Reyner,  356 

Richard,  359 

Richardson,  274,  318 

Richter,  185,  334 

Rieder,    159,    179,  180,   191,   192,   201, 

255»  3^3^  3SS,  397,  435 


Rigler,  334 
Rindfleisch,  142 
Ritchie,  406 
Rodier,  106,  354 
Roger,  87 
Rolleston,  286 
Rollet,  127 
Romberg,  439 
Rosin,  119 
Ross,  360 
Rost,  402 
Rotch,  281 
Roy,  75 
RumpfF,  96 
Russell,  385 

OAILER,  394 

^     Samrazes,  353 

Sanarelli,  1 13,  450 

Sarnow,  419 

Schafer,  134 

Schaffer,  127 

Schaumann,  356 

Schiff.  280 

Schlesinger,  313 

Schmaltz,  99 

Schmidt,  99,  304,    334 

Schneyer,  388 

Scholz,  318 

Schottmiiller,  317 

Schreiber,  195 

Schultz,  187 

Schultz-Schultzenstein,  96 

Schultze,  155,  355 

Schiitze,  88 

Schwinge,  13 1 

Sfameni,  131,  181 

Shaw,  261 

Sherrington,  41,  164,  185,  202,  305 

Silvestrini,  412 

Simon,  1 10,  176 

Sippy,  234 

Sittmann,  308,  392,  411,  428 

Slaughter,  335 

Slawyk,  354 

Smith,  394 

Smyth,  404,  405 

Sobotka,  445 

Solley,  62 

Somers,  404 

Sommerfeld,  424 

Sorby,  8 1 

Sorensen,  131,  400 

Spencer,  402 

Stengel,   50,    135,   151,   183,  289,  350, 

417,  446 
Stephens,  383 
Stern,  318 

Sternberg,  359,  450,  451 
Stierlin,  134 


474 


INDEX    OF    AUTHORS. 


Stockman,  120 
Stokes,  151 
Straus,  304 
Strauss,  96,  334 
Streker,  358 
Stump,  436 
Symes,  428 

T-ALLQUIST,  39,  417 

•*■      Tassinari,  96 
Taylor,  202,  247,  248,  261 
Tchlenorff,  98 
Teichmann,  120 

Thayer,  162,   181,  211,   215,   286,   326. 
329'  330.  359,  361,  368,  369,  379,  392 

Theodor,  287 

Thiemich,  318 

Thoma,  40,  42,  159 

Thomas,  98 

Toisson,  41 

Triboulet,  113,  422 

Trinkler,  108,  3S5 

Tschirkoft,  299 

Tschistowitch,  406 

Tumas,  159,  444 

TUrk,  171,  245,  332,  397,  423 

Tuttle,  84,  317,  392,  399,  412,  429 

Tyson,  272 


U 


HLENMUTH,  88 
Uskow,  173 


WAILLANT,  417 
•       Vail  lard,  244 
Van  den  Berg,  423,  425,  426 
Van  Gieson,  355 
Van  Emden,  228,  239 
Vasquez,  272 
Vast,  417 
Viault,  133 
Vicarelli,  135 
Vincent,  355 
von  Bockmann,  421 


von  Fleischl,  25 

von  Jaksch,  96,  98,  108,  no,  124,  290, 

334,  399,  406,  414,  419] 
von  Lerber,  193 

von  Limbeck,  96,  133,  135,  159,  179, 
188,  195,  228,  237,  255,  332,  334, 

351,  353,  399,  406,  421,  448,  449 
von  Noorden,  143,  147,  199,^306 
Vorbach,  346 
Vulpius,  273 

VUALDVOGEL,  220 
•*       Warren,  273 
Warthin,  128 
Wassermann,  88 
Watson,  347 
Weber,  395,  448 
Wegefarth,  151 
Weil,  262,  449 
Weiss,  158,  174 
Welch,  83,  428 
AVentworth,  178 
White,  180,  289,  399,  411,  428 
Whitney,  178 
Widal,  87,  322,  448 
Widowitz,  425 
Wilkinson,  195,  198 
Williams,  397 
Williamson,  77,  309 
Wiltschour,  317 
Winiarski,  358 
Winternitz,  18 1,  194,  204 
Wolff,  133 
Wood,  356,  450 
Wright,  80,  348,  349,  394 
Wyss,  416 

VERSIN,  306 
^      Young,   299 

VANDY,  195 

^     Zappert,  44,  199,  425 

Zuntz,  96 


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